Viral polymerase inhibitors

ABSTRACT

The present invention relates to viral polymerase inhibitors of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof, processes for their preparation and their use in the treatment of Flaviviridae viral infections such as Hepatitis C virus (HCV) infections.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/623,013, which was filed on Apr. 11, 2012, and U.S. ProvisionalApplication No. 61/623,021, which was filed on Apr. 11, 2012, both ofwhich are incorporated herein by reference in their entirety.

FIELD

The present invention relates to viral polymerase inhibitors, inparticular inhibitors of viral polymerases within the Flaviviridaefamily such as hepatitis C virus (HCV), processes for their preparationand their use in the treatment of Flaviviridae viral infections such asHepatitis C virus (HCV) infections.

BACKGROUND

The Flaviviridae are a group of positive single-stranded RNA viruseswith a genome size from 9-15 kb. The Flaviviridae consist of variousgenera including: Hepaciviruses (this genus contains only one species,the Hepatitis C virus (HCV), which is composed of many genotypes andsubtypes); Flaviviruses (this genus includes the Dengue virus, JapaneseTick-Borne and the Yellow Fever virus and there are some additionalFlaviviruses that are unclassified) and Pestiviruses (this genusincludes three serotypes of bovine viral diarrhoea virus, but no knownhuman pathogens).

Hepatitis C virus (HCV) is a major cause of viral hepatitis and hasinfected more than 200 million people worldwide. Hepatitis C virus has apositive-strand RNA genome enclosed in a nucleocapsid and lipidenvelope. The HCV genome is approximately 9.6 kb in length and encodes apolyprotein of about 3,000 amino acids. There are at least six majorgenotypes, which have different geographic distributions. In the UnitedStates (US), for example, genotypes 1a and 1b account for about 75% ofcases, and genotypes 2 and 3 for 10-20% of cases. Significantdifferences are observed in the geographic distribution of HCVgenotypes. For example, in Europe genotypes 2 and 3 comprise up to onehalf of cases whereas genotype 3 is thought to dominate in India. Inaddition, varied genotype distributions can be observed betweencountries in a particular region as well as in different areas of agiven nation. In the US, HCV is the most common chronic blood-borneinfection, affecting approximately 3.2 million persons. After infectionwith HCV, approximately 75-85% of people develop chronic infection,whilst 60-70% develop chronic liver disease. Of these, 5-20% go on todevelop cirrhosis over a period of 20-30 years, and, finally, 1-5%succumb to the consequences of chronic infection (livercancer/cirrhosis).

Until recently, the only treatment option for HCV was 24 or 48 weeks ofcombination therapy consisting of weekly injections of pegylatedinterferon (peg-IFN) and oral ribavirin for 24 or 48 weeks. The besttreatment response is seen in patients with HCV genotypes 2 and 3, inwhom sustained viral response (SVR) rates of approximately 80% can beachieved with 24 weeks of therapy. Patients with HCV genotype 1 remainthe most difficult to treat, with SVR rates of approximately 40% after48 weeks of therapy. In addition to the low response rates, combinationpeg-IFN/ribavirin therapy is limited by serious side effects, includingfatigue, influenza-like symptoms, depression and suicide with peg-IFN,and haemolytic anaemia with ribavirin. Furthermore, peg-IFN/ribavirintherapy is contra-indicated in patients who have depression, anaemia,HCV-related decompensated cirrhosis, alcohol/substance abuse andautoimmune disorders or who are pregnant.

New treatment options for HCV became available in May 2011 with the USlaunch of the first direct-acting antiviral (DAA) HCV drugs, telaprevir(Vertex Pharmaceuticals) and boceprevir (Merck). Both drugs are proteaseinhibitors and are approved for the treatment of chronic HCV genotype 1infection in combination with peg-IFN and ribavirin. Pivotal phase 3trials demonstrated that the addition of telaprevir or boceprevir topeg-IFN/ribavirin therapy achieved shortened durations of therapy andpotent viral suppression, with SVR rates approaching 75% in genotype 1treatment-naive patients and 30% to 85% in treatment-experiencedpatients.

However, addition of a third drug to the treatment regimen has resultedin increased adverse events. Telaprevir is associated with an increasedincidence of rash and anaemia, while boceprevir is associated withanaemia and dysgeusia. Triple therapy with telaprevir or boceprevir andpeg-IFN/ribavirin remains unsuitable for those intolerant to or withcontraindications to peg-IFN/ribavirin therapy.

Further, the majority of compounds that are currently in developmenthave a limited spectrum of activity against the various HCV genotypesand, in many cases, are only active against HCV genotypes 1b and/or 1a.

The HCV genome possesses structural (core) and non-structural (NS2, NS3,NS4A, NS4B, NS5A and NS5B) proteins. The non-structural proteins areinvolved in viral genomic replication, with the initial synthesis of RNAcarried out by NS5B RNA dependent RNA polymerase. The NS5B protein is akey target for anti-HCV therapy, as it is essential for HCV replicationand has no human host equivalent. This protein has been wellcharacterised and is a validated target for drug discovery.

HCV therapy is also anticipated to evolve towards oral multidrugtherapy, in which combinations of different DAA drugs with complementarymechanisms of action serve to increase viral suppression and delay orprevent the emergence of resistance.

Due to the limited tolerability, efficacy, side effects and concern overthe emergence of resistance there is an ongoing need to find alternativeagents for the treatment of HCV, particularly with targeted mechanismsof action such as NS5B inhibitors.

SUMMARY

The inventors have found a new class of NS5B polymerase inhibitors forthe treatment of HCV infections.

Compounds of the present invention are therefore considered to be usefulin treating and preventing hepatitis C infections when used on their ownor in combination with one or more other antiviral agents such asribavirin, an antiviral nucleoside, polymerase inhibitor, proteaseinhibitor and/or inhibitor of viral entry, assembly or egress. Thecombination may also additionally comprise at least one immunomodulatoryagent for example an interferon or interferon derivative and/or aninhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH).

It is also believed that compounds of the invention will be efficaciousin combination with at least one other DAA with a different mechanism ofaction and a complementary resistance profile (for example an NS5Ainhibitor, a nucleoside or nucleotide NS5B inhibitor or a NS3 proteaseinhibitor) thereby offering an alternative treatment regime for patientsnot eligible for or treatable with the recently approved triplecombination therapy.

According to a first aspect there is provided a compound of formula (I),salts, N-oxides, solvates, hydrates, racemates, enantiomers ordiastereomers thereof:

whereinZ₁ and Z₂ are each independently selected from C—H, C-halo, C—C₁₋₄alkyl,C—C₁₋₄alkylhalo, C—C₁₋₄alkoxy, C—C₁₋₄alkoxyhalo and N;R₁ is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,halo, C₁₋₄alkylhalo, C₁₋₄alkoxyhalo, C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl,5-6-membered heterocyclyl and 5-6 membered heteroaryl and wherein alkyl,alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl and heteroaryl ineach occurrence may be optionally substituted;R₂ is an optionally substituted 4-membered heterocyclic ring;R₃ is selected from aryl, aryl-X-aryl, aryl-X-heteroaryl, heteroaryl,heteroaryl-X-heteroaryl, and heteroaryl-X-aryl wherein X is[C(R₅)₂]_(p), O, S, S(═O), SO₂, NR₅, C═O, CF₂, C(═O)NR₅ or NR₅C(═O)wherein p is 1, 2 or 3 and wherein aryl and heteroaryl in eachoccurrence may be optionally substituted and further wherein aryl ispreferably phenyl and heteroaryl is preferably 5-6-membered heteroaryl;R₄ is H, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, or C₃₋₇cycloalkylpreferably C₁₋₄alkyl;R₅ in each occurrence is independently H or optionally substitutedC₁₋₆alkyl;m represents an integer selected from 0, 1, 2, 3, 4, 5 and 6; andeach (CH₂) moiety when present may be independently optionallysubstituted with one or two substituents;and further when m is an integer selected from 1, 2, 3, 4, 5 and 6 thenone or more (CH₂) may be replaced with O, C═O, NH, optionallysubstituted NC₁₋₆alkyl, S, S═O or SO₂.

In a preferred embodiment R₂ is an optionally substituted azetidine oran optionally substituted oxetane. Optionally substituted oxetanes areparticularly preferred.

According to a second aspect there is provided a process for producingthe compound of formula (I) defined above comprising the step ofcoupling a compound of formula (II):

with a compound of general formula (III) under coupling conditions;whereinW is hydroxyl, mesylate, tosylate, triflate or halo; andZ₁, Z₂, R₁, R₂, R₃, R₄, R₅ and (CH₂)_(m) are as previously defined.

Alternatively, the moiety R₂ may be introduced post-coupling of asuitable precursor moiety to a compound of formula (II), for example, aprecursor containing a diol or alkene group which is subsequentlyfunctionalised to the desired R₂ moiety under suitable ring formingconditions.

Some of the compounds of formula (II) are believed to be novel and alsofall within the scope of the present invention, particularly compoundsin which R₃ is an optionally substituted 2-pyridyl.

The compounds of formula (I) are inhibitors of HCV. In particular, thecompounds of formula (I) inhibit RNA synthesis by the RNA dependent RNApolymerase of HCV (the NS5B protein encoded by HCV). NS5B inhibitorshave been clinically validated as potential antiviral agents for thetreatment of HCV infection.

According to a third aspect, there is provided a pharmaceutical agentcomprising the compound of formula (I) or salts, N-oxides, solvates,hydrates, racemates, enantiomers or diastereomers thereof as definedabove, optionally in combination with another HCV antiviral agent.

There is also provided use of the compound of formula (I) or salts,N-oxides, solvates, hydrates, racemates, enantiomers or diastereomersthereof as defined above as a pharmaceutical agent, optionally incombination with another HCV antiviral agent.

There is further provided the compound of formula (I) or salts,N-oxides, solvates, hydrates, racemates, enantiomers or diastereomersthereof as defined above for use as a pharmaceutical agent, optionallyin combination with another HCV antiviral agent.

The pharmaceutical agent may be an antiviral agent.

According to a fourth aspect, there is provided a viral polymeraseinhibitor in particular a HCV polymerase inhibitor such as a NS5Binhibitor comprising the compound of formula (I) or salts, N-oxides,solvates, hydrates, racemates, enantiomers or diastereomers thereof asdefined above, optionally in combination with another HCV antiviralagent.

There is also provided use of the compound of formula (I) or salts,N-oxides, solvates, hydrates, racemates, enantiomers or diastereomersthereof as defined above as a viral polymerase inhibitor in particular aHCV polymerase inhibitor such as a NS5B inhibitor, optionally incombination with another HCV antiviral agent.

There is further provided the compound of formula (I) or salts,N-oxides, solvates, hydrates, racemates, enantiomers or diastereomersthereof as defined above for use as a viral polymerase inhibitor inparticular a HCV polymerase inhibitor such as a NS5B inhibitor,optionally in combination with another HCV antiviral agent.

The compound of formula (I) or salts, N-oxides, solvates, hydrates,racemates, enantiomers or diastereomers thereof as may be administeredin the form of a pharmaceutical composition together with apharmaceutically acceptable carrier, optionally in combination withanother HCV antiviral agent.

According to a fifth aspect, there is provided a pharmaceuticalcomposition comprising the compound of formula (I) or salts, N-oxides,solvates, hydrates, racemates, enantiomers or diastereomers thereof anda pharmaceutically acceptable carrier.

According to one embodiment, the pharmaceutical composition additionallycomprises a therapeutically effective amount of one or more antiviralagents such as at least one other HCV antiviral agent.

According to a sixth aspect, there is provided a method for thetreatment of a Flaviviridae viral infection such as a HCV infectionwhich comprises administering an effective amount of the compound offormula (I) or salts, N-oxides, solvates, hydrates, racemates,enantiomers or diastereomers thereof as defined above or thepharmaceutical agent or pharmaceutical composition defined above,optionally in combination with another HCV antiviral agent to a subjectin need thereof.

There is also provided use of the compound of formula (I) or salts,N-oxides, solvates, hydrates, racemates, enantiomers or diastereomersthereof as defined above or the pharmaceutical agent or pharmaceuticalcomposition as defined above in the manufacture of a medicament for usein the treatment of a Flaviviridae viral infection such as a HCVinfection, optionally in combination with another HCV antiviral agent.

There is further provided use of the compound of formula (I) or salts,N-oxides, solvates, hydrates, racemates, enantiomers or diastereomersthereof as defined above or the pharmaceutical agent or pharmaceuticalcomposition as defined above, optionally in combination with another HCVantiviral agent in the treatment of a Flaviviridae viral infection suchas a HCV infection.

There is still further provided the compound of the formula (I) orsalts, N-oxides, solvates, hydrates, racemates, enantiomers ordiastereomers thereof as defined above or the pharmaceutical agent orpharmaceutical composition defined above, optionally in combination withanother HCV antiviral agent for use in the treatment of a Flaviviridaeviral infection such as a HCV infection.

According to a seventh aspect, there is provided a method of inhibitingthe RNA-dependent RNA polymerase activity of the enzyme NS5B, encoded byHCV, comprising exposing the enzyme NS5B to an effective amount of thecompound of formula (I) or salts, N-oxides, solvates, hydrates,racemates, enantiomers or diastereomers thereof as defined above,optionally in combination with another HCV antiviral agent.

According to an eighth aspect, there is provided a method of inhibitingHCV replication comprising exposing a cell infected with HCV to aneffective amount of the compound of formula (I) or pharmaceuticallyacceptable salts, N-oxides, solvates, hydrates, racemates, enantiomersor diastereomers thereof as defined above, optionally in combinationwith another HCV antiviral agent.

DETAILED DESCRIPTION

The present invention is predicated on the discovery of a new class ofcompounds that have been shown to inhibit viral polymerases, moreparticularly NS5B polymerases. Accordingly in one embodiment thecompounds of formula (I) are useful in the treatment of Flaviviridaeviral infections, particularly, hepatitis C (HCV).

Applicant's earlier filed U.S. Ser. No. 13/278,021 and WO2012/051659(PCT/AU2011/001336) are directed to a structurally related class ofcompounds. However, the compounds of the present invention are notspecifically described therein and further have demonstrated goodactivity, generally in the nanomolar range(s) of the earlierapplications.

The compounds are also believed to possess one or more advantageouspharmaceutical properties including solubility and/or metabolicstability.

DEFINITIONS

Unless otherwise herein defined, the following terms will be understoodto have the general meanings which follow.

The term “C₁₋₆alkyl” refers to optionally substituted straight chain orbranched chain hydrocarbon groups having from 1 to 6 carbon atoms.Examples include methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr),butyl (Bu), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu),pentyl, neopentyl, hexyl and the like. Unless the context requiresotherwise, the term “C₁₋₆alkyl” also encompasses alkyl groups containingone less hydrogen atom such that the group is attached via two positionsi.e. divalent. “C₁₋₄alkyl” and “C₁₋₃alkyl” including methyl, ethyl,propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl arepreferred with methyl being particularly preferred.

The term “C₂₋₆alkenyl” refers to optionally substituted straight chainor branched chain hydrocarbon groups having at least one double bond ofeither E or Z stereochemistry where applicable and 2 to 6 carbon atoms.Examples include vinyl, 1-propenyl, 1- and 2-butenyl and2-methyl-2-propenyl. Unless the context requires otherwise, the term“C₂₋₆alkenyl” also encompasses alkenyl groups containing one lesshydrogen atom such that the group is attached via two positions i.e.divalent. “C₂₋₄alkenyl” and “C₂₋₃alkenyl” including ethenyl, propenyland butenyl are preferred with ethenyl being particularly preferred.

The term “C₂₋₆alkynyl” refers to optionally substituted straight chainor branched chain hydrocarbon groups having at least one triple bond and2 to 6 carbon atoms. Examples include ethynyl, 1-propynyl, 1- and2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl and the like. Unless thecontext indicates otherwise, the term “C₂₋₆alkynyl” also encompassesalkynyl groups containing one less hydrogen atom such that the group isattached via two positions i.e. divalent. C₂₋₃alkynyl is preferred.

The term “C₃₋₈cycloalkyl” refers to non-aromatic cyclic groups havingfrom 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. It will beunderstood that cycloalkyl groups may be saturated such as cyclohexyl orunsaturated such as cyclohexenyl. C₃₋₆cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl are preferred.

The terms “hydroxy” and “hydroxyl” refer to the group —OH.

The term “oxo” refers to the group ═O.

The term “C₁₋₆alkoxy” refers to an alkyl group as defined abovecovalently bound via an O linkage containing 1 to 6 carbon atoms, suchas methoxy, ethoxy, propoxy, isoproxy, butoxy, tert-butoxy and pentoxy.“C₁₋₄alkoxy” and “C₁₋₃ alkoxy” including methoxy, ethoxy, propoxy andbutoxy are preferred with methoxy being particularly preferred.

The term “C₁₋₆alkylhalo” refers to a C₁₋₆alkyl which is substituted withone or more halogens. C₁₋₃alkylhalo groups are preferred, such as forexample, —CHF₂ and —CF₃.

The term “C₁₋₆alkoxyhalo” refers to a C₁₋₆alkoxy which is substitutedwith one or more halogens. C₁₋₃alkoxyhalo groups are preferred, such asfor example, —OCHF₂ and —OCF₃.

The term “carboxylate” or “carboxyl” refers to the group —COO⁻ or —COOH.

The term “ester” refers to a carboxyl group having the hydrogen replacedwith, for example a C₁₋₆alkyl group (“carboxylC₁₋₆alkyl” or“alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”)and so on. CO₂C₁₋₃alkyl groups are preferred, such as for example,methylester (CO₂Me), ethylester (CO₂Et) and propylester (CO₂Pr) andincludes reverse esters thereof (e.g. —OCOMe, —OCOEt and —OCOPr).

The term “cyano” refers to the group —CN.

The term “nitro” refers to the group —NO₂.

The term “amino” refers to the group —NH₂.

The term “substituted amino” or “secondary amino” refers to an aminogroup having a hydrogen replaced with, for example a C₁₋₆alkyl group(“C₁₋₆alkylamino”), an aryl or aralkyl group (“arylamino”,“aralkylamino”) and so on. C₁₋₃alkylamino groups are preferred, such asfor example, methylamino (NHMe), ethylamino (NHEt) and propylamino(NHPr).

The term “disubstituted amino” or “tertiary amino” refers to an aminogroup having the two hydrogens replaced with, for example a C₁₋₆alkylgroup, which may be the same or different (“dialkylamino”), an aryl andalkyl group (“aryl(alkyl)amino”) and so on. Di(C₁₋₃alkyl)amino groupsare preferred, such as for example, dimethylamino (NMe₂), diethylamino(NEt₂), dipropylamino (NPr₂) and variations thereof (e.g. N(Me)(Et) andso on).

The term “acyl” or “aldehyde” refers to the group —C(═O)H.

The term “substituted acyl” or “ketone” refers to an acyl group having ahydrogen replaced with, for example a C₁₋₆alkyl group (“C₁₋₆alkylacyl”or “alkylketone” or “ketoalkyl”), an aryl group (“arylketone”), anaralkyl group (“aralkylketone) and so on. C₁₋₃alkylacyl groups arepreferred.

The term “amido” or “amide” refers to the group —C(O)NH₂.

The term “aminoacyl” refers to the group —NHC(O)H.

The term “substituted amido” or “substituted amide” refers to an amidogroup having a hydrogen replaced with, for example a C₁₋₆alkyl group(“C₁₋₆alkylamido” or “C₁₋₆alkylamide”), an aryl (“arylamido”), aralkylgroup (“aralkylamido”) and so on. C₁₋₃alkylamide groups are preferred,such as for example, methylamide (—C(O)NHMe), ethylamide (—C(O)NHEt) andpropylamide (—C(O)NHPr) and includes reverse amides thereof (e.g.—NHMeC(O)—, —NHEtC(O)— and —NHPrC(O)—).

The term “disubstituted amido” or “disubstituted amide” refers to anamido group having the two hydrogens replaced with, for example aC₁₋₆alkyl group (“di(C₁₋₆alkyl)amido” or “di(C₁₋₆alkyl)amide”), anaralkyl and alkyl group (“alkyl(aralkyl)amido”) and so on.Di(C₁₋₃alkyl)amide groups are preferred, such as for example,dimethylamide (—C(O)NMe₂), diethylamide (—C(O)NEt₂) and dipropylamide((—C(O)NPr₂) and variations thereof (e.g. —C(O)N(Me)Et and so on) andincludes reverse amides thereof.

The term “thiol” refers to the group —SH.

The term “C₁₋₆alkylthio” refers to a thiol group having the hydrogenreplaced with a C₁₋₆alkyl group. C₁₋₃alkylthio groups are preferred,such as for example, thiolmethyl, thiolethyl and thiolpropyl.

The term “thioxo” refers to the group ═S.

The term “sulfinyl” refers to the group —S(═O)H.

The term “substituted sulfinyl” or “sulfoxide” refers to a sulfinylgroup having the hydrogen replaced with, for example a C₁₋₆alkyl group(“C₁₋₆alkylsulfinyl” or “C₁₋₆alkylsulfoxide”), an aryl (“arylsulfinyl”),an aralkyl (“aralkyl sulfinyl”) and so on. C₁₋₃alkylsulfinyl groups arepreferred, such as for example, —SOmethyl, —SOethyl and —SOpropyl.

The term “sulfonyl” refers to the group —SO₂H.

The term “substituted sulfonyl” refers to a sulfonyl group having thehydrogen replaced with, for example a C₁₋₆alkyl group(“sulfonylC₁₋₆alkyl”), an aryl (“arylsulfonyl”), an aralkyl(“aralkylsulfonyl”) and so on. SulfonylC₁₋₃alkyl groups are preferred,such as for example, —SO₂Me, —SO₂Et and —SO₂Pr.

The term “sulfonylamido” or “sulfonamide” refers to the group —SO₂NH₂.

The term “substituted sulfonamido” or “substituted sulphonamide” refersto an sulfonylamido group having a hydrogen replaced with, for example aC₁₋₆alkyl group (“sulfonylamidoC₁₋₆alkyl”), an aryl (“arylsulfonamide”),aralkyl (“aralkylsulfonamide”) and so on. SulfonylamidoC₁₋₃alkyl groupsare preferred, such as for example, —SO₂NHMe, —SO₂NHEt and —SO₂NHPr andincludes reverse sulfonamides thereof (e.g. —NHSO₂Me, —NHSO₂Et and—NHSO₂Pr).

The term “disubstituted sulfonamido” or “disubstituted sulphonamide”refers to an sulfonylamido group having the two hydrogens replaced with,for example a C₁₋₆alkyl group, which may be the same or different(“sulfonylamidodi(C₁₋₆alkyl)”), an aralkyl and alkyl group(“sulfonamido(aralkyl)alkyl”) and so on. Sulfonylamidodi(C₁₋₃alkyl)groups are preferred, such as for example, —SO₂NMe₂, —SO₂NEt₂ and—SO₂NPr₂ and variations thereof (e.g. —SO₂N(Me)Et and so on) andincludes reserve sulfonamides thereof.

The term “sulfate” refers to the group OS(O)₂OH and includes groupshaving the hydrogen replaced with, for example a C₁₋₆alkyl group(“alkylsulfates”), an aryl (“arylsulfate”), an aralkyl(“aralkylsulfate”) and so on. C₁₋₃sulfates are preferred, such as forexample, OS(O)₂OMe, OS(O)₂OEt and OS(O)₂OPr.

The term “sulfonate” refers to the group SO₃H and includes groups havingthe hydrogen replaced with, for example a C₁₋₆alkyl group(“alkylsulfonate”), an aryl (“arylsulfonate”), an aralkyl(“aralkylsulfonate”) and so on. C₁₋₃sulfonates are preferred, such asfor example, SO₃Me, SO₃Et and SO₃Pr.

The term “aryl” refers to a carbocyclic (non-heterocyclic) aromatic ringor mono-, bi- or tri-cyclic ring system. The aromatic ring or ringsystem is generally composed of 6 to 10 carbon atoms. Examples of arylgroups include but are not limited to phenyl, biphenyl, naphthyl andtetrahydronaphthyl. 6-membered aryls such as phenyl are preferred. Theterm “alkylaryl” refers to C₁₋₆alkylaryl such as benzyl.

The term “alkoxyaryl” refers to C₁₋₆alkyloxyaryl such as benzyloxy.

The term “heterocyclyl” refers to a moiety obtained by removing ahydrogen atom from a ring atom of a heterocyclic compound which moietyhas from 3 to 10 ring atoms (unless otherwise specified), of which 1, 2,3 or 4 are ring heteroatoms each heteroatom being independently selectedfrom O, S and N.

In this context, the prefixs 3-, 4-, 5-, 6-, 7-, 8-, 9- and 10-membereddenote the number of ring atoms, or range of ring atoms, whether carbonatoms or heteroatoms. For example, the term “3-10 membered heterocylyl”,as used herein, pertains to a heterocyclyl group having 3, 4, 5, 6, 7,8, 9 or 10 ring atoms. Examples of heterocylyl groups include5-6-membered monocyclic heterocyclyls and 9-10 membered fused bicyclicheterocyclyls.

Examples of monocyclic heterocyclyl groups include, but are not limitedto, those containing one nitrogen atom such as aziridine (3-memberedring), azetidine (4-membered ring), pyrrolidine (tetrahydropyrrole),pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole), 2H-pyrrole or3H-pyrrole (isopyrrole, isoazole) or pyrrolidinone (5-membered rings),piperidine, dihydropyridine, tetrahydropyridine (6-membered rings), andazepine (7-membered ring); those containing two nitrogen atoms such asimidazoline, pyrazolidine (diazolidine), imidazoline, pyrazoline(dihydropyrazole) (5-membered rings), piperazine (6-membered ring);those containing one oxygen atom such as oxirane (3-membered ring),oxetane (4-membered ring), oxolane (tetrahydrofuran), oxole(dihydrofuran) (5-membered rings), oxane (tetrahydropyran),dihydropyran, pyran (6-membered rings), oxepin (7-membered ring); thosecontaining two oxygen atoms such as dioxolane (5-membered ring), dioxane(6-membered ring), and dioxepane (7-membered ring); those containingthree oxygen atoms such as trioxane (6-membered ring); those containingone sulfur atom such as thiirane (3-membered ring), thiepane (4-memberedring), thiolane (tetrahydrothiophene) (5-membered ring), thiane(tetrahydrothiopyran) (6-membered ring), thiepane (7-membered ring);those containing one nitrogen and one oxygen atom such astetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole(5-membered rings), morpholine, tetrahydrooxazine, dihydrooxazine,oxazine (6-membered rings); those containing one nitrogen and one sulfuratom such as thiazoline, thiazolidine (5-membered rings), thiomorpholine(6-membered ring); those containing two nitrogen and one oxygen atomsuch as oxadiazine (6-membered ring); those containing one oxygen andone sulfur such as: oxathiole (5-membered ring) and oxathiane (thioxane)(6-membered ring); and those containing one nitrogen, one oxygen and onesulfur atom such as oxathiazine (6-membered ring).

Heterocyclyls also encompass aromatic heterocyclyls and non-aromaticheterocyclyls. Such groups may be substituted or unsubstituted.

The term “aromatic heterocyclyl” may be used interchangeably with theterm “heteroaromatic” or the term “heteroaryl” or “hetaryl”. Theheteroatoms in the aromatic heterocyclyl group may be independentlyselected from N, S and O.

“Heteroaryl” is used herein to denote a heterocyclic group havingaromatic character and embraces aromatic monocyclic ring systems andpolycyclic (e.g. bicyclic) ring systems containing one or more aromaticrings. The term aromatic heterocyclyl also encompasses pseudoaromaticheterocyclyls. The term “pseudoaromatic” refers to a ring system whichis not strictly aromatic, but which is stabilized by means ofdelocalization of electrons and behaves in a similar manner to aromaticrings. The term aromatic heterocyclyl therefore covers polycyclic ringsystems in which all of the fused rings are aromatic as well as ringsystems where one or more rings are non-aromatic, provided that at leastone ring is aromatic. In polycyclic systems containing both aromatic andnon-aromatic rings fused together, the group may be attached to anothermoiety by the aromatic ring or by a non-aromatic ring.

Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to ten ring members. The heteroaryl group can be,for example, a five membered or six membered monocyclic ring or abicyclic structure formed from fused five and six membered rings or twofused six membered rings or two fused five membered rings. Each ring maycontain up to about four heteroatoms typically selected from nitrogen,sulphur and oxygen. The heteroaryl ring will contain up to 4heteroatoms, more typically up to 3 heteroatoms, more usually up to 2,for example a single heteroatom. In one embodiment, the heteroaryl ringcontains at least one ring nitrogen atom. The nitrogen atoms in theheteroaryl rings can be basic, as in the case of an imidazole orpyridine, or essentially non-basic as in the case of an indole orpyrrole nitrogen. In general the number of basic nitrogen atoms presentin the heteroaryl group, including any amino group substituents of thering, will be less than five.

Aromatic heterocyclyl groups may be 5-membered or 6-membered mono-cyclicaromatic ring systems.

Examples of 5-membered monocyclic heteroaryl groups include but are notlimited to furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including1,2,3 and 1,2,4 oxadiazolyls and furazanyl i.e. 1,2,5-oxadiazolyl),thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl(including 1,2,3, 1,2,4 and 1,3,4 triazolyls), oxatriazolyl, tetrazolyl,thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls) and the like.

Examples of 6-membered monocyclic heteroaryl groups include but are notlimited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl and the like.Examples of 6-membered aromatic heterocyclyls containing nitrogeninclude pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2nitrogens).

Aromatic heterocyclyl groups may also be bicyclic or polycyclicheteroaromatic ring systems such as fused ring systems (includingpurine, pteridinyl, napthyridinyl, 1H thieno[2,3-c]pyrazolyl,thieno[2,3-b]furyl and the like) or linked ring systems (such asoligothiophene, polypyrrole and the like). Fused ring systems may alsoinclude aromatic 5-membered or 6-membered heterocyclyls fused tocarbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl,fluorenyl, anthracenyl and the like, such as 5-membered aromaticheterocyclyls containing nitrogen fused to phenyl rings, 5-memberedaromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.

A bicyclic heteroaryl group may be, for example, a group selected from:a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ringcontaining 1, 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrolering fused to a 5- or 6-membered ring containing 1, 2 or 3 ringheteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ringcontaining 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5-or 6-membered ring containing 1 or 2 ring heteroatoms; g) an oxazolering fused to a 5- or 6-membered ring containing 1 or 2 ringheteroatoms; h) an isoxazole ring fused to a 5- or 6-membered ringcontaining 1 or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or6-membered ring containing 1 or 2 ring heteroatoms; j) an isothiazolering fused to a 5- or 6-membered ring containing 1 or 2 ringheteroatoms; k) a thiophene ring fused to a 5- or 6-membered ringcontaining 1, 2 or 3 ring heteroatoms; l) a furan ring fused to a 5- or6-membered ring containing 1, 2 or 3 ring heteroatoms; m) a cyclohexylring fused to a 5- or 6-membered ring containing 1, 2 or 3 ringheteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered ringcontaining 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a fivemembered ring fused to another five membered ring include but are notlimited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) andimidazoimidazole (e.g. imidazo[1,2-a]imidazole).

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzofuran, benzothiophene, benzimidazole, benzoxazole,isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole,isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline,purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g.pyrazolo[1,5-a]pyrimidine)benzodioxole and pyrazolopyridine (e.g.pyrazolo[1,5-a]pyridine) groups. A further example of a six memberedring fused to a five membered ring is a pyrrolopyridine group such as apyrrolo[2,3-b]pyridine group.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinoline,isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman,benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine,quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine andpteridine groups.

Examples of heteroaryl groups containing an aromatic ring and anon-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline,tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran,2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole,4,5,6,7-tetrahydrobenzofuran, indoine, isoindoline and indane groups.

Examples of aromatic heterocyclyls fused to carbocyclic aromatic ringsmay therefore include but are not limited to benzothiophenyl, indolyl,isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl,benzoxazolyl, benzisoxazolyl, isobenzoxazoyl, benzothiazolyl,benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl,cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl and the like.

The term “non-aromatic heterocyclyl” encompasses optionally substitutedsaturated and unsaturated rings which contain at least one heteroatomselected from the group consisting of N, S and O.

Non-aromatic heterocyclyls may be 3-7 membered mono-cyclic rings.

Examples of 5-membered non-aromatic heterocyclyl rings include2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl,1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrazolinyl, 2-pyrazolinyl, 3-pyrazolinyl,pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl,3-dioxalanyl, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl and thelike.

Examples of 6-membered non-aromatic heterocyclyls include piperidinyl,piperidinonyl, pyranyl, dihyrdopyranyl, tetrahydropyranyl, 2H pyranyl,4H pyranyl, thianyl, thianyl oxide, thianyl dioxide, piperazinyl,diozanyl, 1,4-dioxinyl, 1,4-dithianyl, 1,3,5-triozalanyl,1,3,5-trithianyl, 1,4-morpholinyl, thiomorpholinyl, 1,4-oxathianyl,triazinyl, 1,4-thiazinyl and the like.

Examples of 7-membered non-aromatic heterocyclyls include azepanyl,oxepanyl, thiepanyl and the like.

Non-aromatic heterocyclyl rings may also be bicyclic heterocyclyl ringssuch as linked ring systems (for example uridinyl and the like) or fusedring systems. Fused ring systems include non-aromatic 5-membered,6-membered or 7-membered heterocyclyls fused to carbocyclic aromaticrings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyland the like. Examples of non-aromatic 5-membered, 6-membered or7-membered heterocyclyls fused to carbocyclic aromatic rings includeindolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl and thelike.

The term “halo” refers to fluoro, chloro, bromo or iodo.

Unless otherwise defined, the term “optionally substituted” or “optionalsubstituent” as used herein refers to a group which may or may not befurther substituted with 1, 2, 3, 4 or more groups, preferably 1, 2 or3, more preferably 1 or 2 groups selected from the group consisting ofC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, hydroxyl, oxo,C₁₋₆alkoxy, aryloxy, C₁₋₆alkoxyaryl, halo, C₁₋₆alkylhalo (such as CF₃and CHF₂), C₁₋₆alkoxyhalo (such as OCF₃ and OCHF₂), carboxyl, esters,cyano, nitro, amino, substituted amino, disubstituted amino, acyl,ketones, amides, aminoacyl, substituted amides, disubstituted amides,thiol, alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substitutedsulfinyl, sulfonyl, substituted sulfonyl, sulfonylamides, substitutedsulfonamides, disubstituted sulfonamides, aryl, arC₁₋₆alkyl,heterocyclyl and heteroaryl wherein each alkyl, alkenyl, alkynyl,cycloalkyl, aryl and heterocyclyl and groups containing them may befurther optionally substituted. Optional substituents in the case ofheterocycles containing N may also include but are not limited toC₁₋₆alkyl i.e. N—C₁₋₃alkyl, more preferably methyl particularlyN-methyl.

It will be understood that suitable derivatives of aromaticheterocyclyls containing nitrogen include N-oxides thereof.

Compounds

The present invention relates to compounds of formula (I), salts,N-oxides, solvates, hydrates, racemates, enantiomers or diastereomersthereof as defined above.

In one embodiment, there is provided a compound of formula (Ia), salts,N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof

whereinZ₁, Z₂, R₁, R₃, R₄, R₅ and (CH₂)_(m) are as previously defined;W₁ is CR^(a) or N;W₂, W₃ and W₄ are each independently selected from O, NR^(b), S, S═O,SO₂, C═O or CR^(c)R^(d); andR^(a), R^(b), R^(c) and R^(d) are each independently selected from H oran optional substituent as previously defined,with the proviso that one of W₁, W₂, W₃ and W₄ is a heteroatom selectedfrom O, NR^(b) and S, preferably O or NR^(b) and the three remaining areindependently CR¹ in the case of W₁ and CR^(c)R^(d) in the case of anyone of W₂, W₃ and W₄.

In one embodiment W₁ is CR^(a), W₂ is O or NR^(b) and W₃ and W₄ areindependently CR^(c)R^(d).

In another embodiment W₁ is CR^(a), W₃ is O or NR^(b) and W₂ and W₄ areindependently CR^(c)R^(d).

In one embodiment W₁ is N and W₂, W₃ and W₄ are each independentlyCR^(c)R^(d).

In one embodiment R^(a), R^(b), R^(c) and R^(d) are each independentlyselected from H, halo, optionally substituted C₁₋₆alkyl, haloC₁₋₃alkylincluding CHF₂ and CF₃, optionally substituted C₁₋₃alkoxy,haloC₁₋₃alkoxy including OCHF₂ and OCF₃, OH, ═O, C(═O)C₁₋₃alkyl, CN,NO₂, NH₂, optionally substituted NHC₁₋₆alkyl, optionally substitutedN(C₁₋₆alkyl)₂, optionally substituted amides of general formulaNHC(═O)C₁₋₆alkyl, CO₂H and optionally substituted esters of generalformula C(═O)OC₁₋₆alkyl.

In one embodiment R^(a), R^(b), R^(c) and R^(d) are independentlyselected from H, F, optionally substituted C₁₋₃alkyl (preferably methylwhich may be further optionally substituted with NHC(═O)OC₁₋₄alkyl,preferably NHC(═O)O-tert-butyl), C(═O)CH₃, CHF₂, CF₃, OH and methoxy,preferably H, F, methyl, OH and methoxy, even more preferably H andmethyl.

In one embodiment (CH₂)_(m) represents an optionally substitutedmethylenyl (i.e. m=1), ethylenyl (i.e. m=2) or propylenyl (i.e. m=3)moiety, preferably m is 1 or 2.

In one embodiment each (CH₂)_(m) when present may be independentlyoptionally substituted with one or two optional substituents aspreviously defined and preferably selected from the group consisting ofhalo, optionally substituted C₁₋₆alkyl, optionally substitutedC₂₋₆alkenyl, haloC₁₋₃alkyl, OH, ═O, optionally substituted C₁₋₆alkoxy,haloC₁₋₃alkoxyl, CO₂H, optionally substituted esters of general formulaC(═O)OC₁₋₆alkyl, CN, NO₂, NH₂, NHC₁₋₃alkyl, N(C₁₋₃alkyl)₂, optionallysubstituted amides of general formula NHC(═O)C₁₋₆alkyl, an optionallysubstituted C₃₋₇cycloalkyl, an optionally substituted C₆₋₁₀aryl and anoptionally substituted 4-10-membered heterocyclyl.

C₁₋₃alkyl particularly methyl, halo particularly fluoro and C₁₋₃alkoxyparticularly methoxy, are preferred optional substituents for (CH₂) whenpresent with methyl and fluoro being most preferred.

In one embodiment Z₁ and Z₂ are C—H; R₁ is selected from optionallysubstituted C₁₋₃alkyl, C₁₋₃alkoxyl and C₃₋₅cycloalkyl, preferablycyclopropyl; R₃ is an optionally substituted phenyl or an optionallysubstituted 6-membered heteroaryl ring selected from pyridyl,pyridazinyl, pyrimidinyl and pyrazinyl, preferably R₃ is optionallysubstituted phenyl or pyridyl with C₁₋₄alkyl and halo being particularlypreferred optional substituents and methyl or Cl being most preferred;R₄ is an optionally substituted C₁₋₆alkyl, preferably C₁₋₃alkyl and morepreferably is unsubstituted methyl; R₅ is optionally substitutedC₁₋₆alkyl preferably C₁₋₃alkyl optionally substituted with halo such asCF₃ or CHF₂ with methyl being particularly preferred; m is an integerselected from 0, 1, 2 or 3, preferably 1, 2 or 3, even more preferably mis 2; and each —(CH₂)— when present is independently optionallysubstituted with one or two substituents as previously definedpreferably independently selected from halo, C₁₋₄alkyl, haloC₁₋₃alkyland C₁₋₃alkoxy.

In one embodiment the compound is of formula (I) and is selected fromthe group consisting of:

and salts, N-oxides, solvates, hydrates, racemates, enantiomers ordiastereomers thereof wherein the compounds are named as follows:

-   3)    5-cyclopropyl-N-methyl-2-(4-methylphenyl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide;-   4)    2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)[2-(oxetan-2-yl)propyl]amino}-2H-indazole-3-carboxamide;-   5)    5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide;-   6) 6-{[2-(azetidin-3-yl)ethyl](methyl    sulfonyl)amino}-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide;-   7)    2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{[2-(1-methylazetidin-3-yl)ethyl](methylsulfonyl)amino}-2H-indazole-3-carboxamide;-   8)    6-{[2-(1-acetylazetidin-3-yl)ethyl](methylsulfonyl)amino}-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide;-   9)    2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{[2-(2-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-21′-indazole-3-carboxamide;-   10)    2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide;-   11)    2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{[2-(3-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2H-indazole-3-carboxamide;-   12)    2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{[(3-methyloxetan-3-yl)methyl](methylsulfonyl)amino}-2H-indazole-3-carboxamide;-   13)    2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)[2-(oxetan-2-yl)ethyl]amino}-2H-indazole-3-carboxamide;-   14)    2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)(oxetan-3-ylmethyl)amino]-2H-indazole-3-carboxamide;-   15) 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)    [2-(oxetan-3-yl)propyl]amino}-2H-indazole-3-carboxamide;-   16) 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)    {2-[3-(propan-2-yl)oxetan-3-yl]ethyl}amino]-2H-indazole-3-carboxamide;-   17)    3,5-anhydro-1-{[2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)-2H-indazol-6-yl](methylsulfonyl)amino}-1,2,4-trideoxy-4-methylpentitol;-   18)    2-(4-chlorophenyl)-5-cyclopropyl-6-{[2-fluoro-2-(oxetan-3-yl)ethyl](methylsulfonyl)amino}-N-methyl-2H-indazole-3-carboxamide;-   19) tert-butyl    3-(2-{[2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)-2H-indazol-6-yl](methylsulfonyl)amino}ethyl)azetidine-1-carboxylate;-   20)    5-cyclopropyl-N-methyl-6-{[2-(2-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide;-   21)    5-cyclopropyl-N-methyl-6-{[2-(3-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide;-   22)    2-(4-chlorophenyl)-5-cyclopropyl-6-[2-(3-hydroxyazetidin-1-yl)ethyl-methylsulfonyl-amino]-N-methyl-indazole-3-carboxamide;-   24) tert-butyl    3-[2-[[5-cyclopropyl-3-(methylcarbamoyl)-2-(5-methyl-2-pyridyl)indazol-6-yl]-methylsulfonyl-amino]ethyl]azetidine-1-carboxylate;-   25)    6-[2-(1-acetylazetidin-3-yl)ethyl-methylsulfonyl-amino]-5-cyclopropyl-N-methyl-2-(5-methyl-2-pyridyl)indazole-3-carboxamide;-   26)    2-(4-chlorophenyl)-5-cyclopropyl-6-[2-(3-fluorooxetan-3-yl)ethyl-methylsulfonyl-amino]-N-methyl-indazole-3-carboxamide;-   27) tert-butyl    3-[2-[[2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)indazol-6-yl]-methylsulfonyl-amino]ethyl]-3-methoxy-azetidine-1-carboxylate;-   28)    5-cyclopropyl-6-[2-(3-methoxyoxetan-3-yl)ethyl-methylsulfonyl-amino]-N-methyl-2-(5-methyl-2-pyridyl)indazole-3-carboxamide;-   29)    2-(4-chlorophenyl)-5-cyclopropyl-6-[2-(3-methoxyazetidin-3-yl)ethyl-methylsulfonyl-amino]-N-methyl-indazole-3-carboxamide;-   30) 6-[2-(1-acetyl-3-methoxy-azetidin-3-yl)ethyl-methyl    sulfonyl-amino]-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-indazole-3-carboxamide;-   31)    2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[2-[-2-methyloxetan-3-yl]ethyl-methyl    sulfonyl-amino]indazole-3-carboxamide;-   32)    2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[{2-[(2S,3R)-2-methyloxetan-3-yl]ethyl}(methylsulfonyl)amino]-2H-indazole-3-carboxamide;-   33)    2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[{2-[(2R,3S)-2-methyloxetan-3-yl]ethyl}(methylsulfonyl)amino]-2H-indazole-3-carboxamide;-   34)    2-(5-chloro-2-pyridyl)-5-cyclopropyl-N-methyl-6-[methylsulfonyl-[2-(oxetan-3-yl)ethyl]amino]indazole-3-carboxamide;-   35) tert-butyl    N-[[3-[2-[[5-cyclopropyl-3-(methylcarbamoyl)-2-(5-methyl-2-pyridyl)indazol-6-yl]-methylsulfonyl-amino]ethyl]oxetan-3-yl]methyl]carbamate;    and-   36)    2-(4-chlorophenyl)-5-cyclopropyl-6-[2-(3-methoxyoxetan-3-yl)ethyl-methylsulfonyl-amino]-N-methyl-indazole-3-carboxamide.

In one embodiment the compound is of formula (II) and selected from thegroup consisting of:

and salts, N-oxides, solvates, hydrates, racemates, enantiomers ordiastereomers thereof wherein the compounds are named as follows:

-   1)    2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide;-   2)    5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide;    and-   23)    2-(5-chloro-2-pyridyl)-5-cyclopropyl-6-(methanesulfonamido)-N-methyl-indazole-3-carboxamide.

The compounds of the invention may also be prepared as salts which arepharmaceutically acceptable, but it will be appreciated thatnon-pharmaceutically acceptable salts also fall within the scope of thepresent invention, since these are useful as intermediates in thepreparation of pharmaceutically acceptable salts. Examples ofpharmaceutically acceptable salts include salts of pharmaceuticallyacceptable cations such as sodium, potassium, lithium, calcium,magnesium, ammonium and alkylammonium; acid addition salts ofpharmaceutically acceptable inorganic acids such as hydrochloric,orthophosphoric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamicand hydrobromic acids; or salts of pharmaceutically acceptable organicacids such as acetic, propionic, butyric, tartaric, maleic,hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic,succinic, oxalic, phenylacetic, methanesulfonic, trihalomethanesulfonic,toluenesulfonic, benzenesulfonic, isethionic, salicylic, sulphanilic,aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric,pantothenic, tannic, ascorbic, valeric and orotic acids. Salts of aminegroups may also comprise quaternary ammonium salts in which the aminonitrogen atom carries a suitable organic group such as an alkyl,alkenyl, alkynyl or aralkyl moiety.

The salts may be formed by conventional means, such as by reacting thefree base form of the compound with one or more equivalents of theappropriate acid.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, alcohols such as methanol, ethanol orisopropyl alcohol, DMSO, acetonitrile, dimethyl formamide (DMF) and thelike with the solvate forming part of the crystal lattice by eithernon-covalent binding or by occupying a hole in the crystal lattice.Hydrates are formed when the solvent is water, alcoholates are formedwhen the solvent is alcohol. Solvates of the compounds of the presentinvention can be conveniently prepared or formed during the processesdescribed herein. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Additionally, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds of the present invention are also considered to be disclosedherein.

It will be understood that compounds of formula (I) may possess a chiralcentre and may therefore exist as an isomer such as a racemate or an R-or S-enantiomer. The compounds may therefore be used as a purifiedenantiomer or diastereomer, or as a mixture of any ratio thereof. Theisomers may be separated conventionally by chromatographic methods orusing a resolving agent. Alternatively the individual isomers may beprepared by asymmetric synthesis using chiral intermediates. Where thecompound has a carbon-carbon double bond, it may occur in Z- or E-formand all isomeric forms of the compounds being included in the presentinvention.

This invention also encompasses prodrugs of the compounds of formula(I).

The term “pro-drug” is used herein in its broadest sense to includethose compounds which are converted in vivo to the compound of formula(I). Use of the prodrug strategy optimises the delivery of the drug toits site of action. In one embodiment, compounds of formula (I) havingfree amino, amido, hydroxyl, or carboxylic acid groups can be convertedinto prodrugs. Prodrugs include compounds wherein carbonates,carbamates, amide and alkyl esters which are covalently bonded to theabove substituents of compounds of the present invention through acarbonyl carbon prodrug sidechain. Prodrugs may also include N-oxides ofring nitrogen atoms in formula (I).

Viral Polymerase Inhibition

The ability of the compounds of formula (I) to inhibit RNA synthesis bythe RNA dependent RNA polymerase of HCV (NS5B) can be demonstrated byany assay capable of measuring RNA dependent RNA polymerase activity. Asuitable assay is described in the examples.

While the invention is described with particular reference to compoundshaving inhibitory activity against a HCV NS5B polymerase, it will beunderstood that other polymerases can, if desired, be substituted inwhole or in part for the HCV polymerase herein described. For example,one microbial polymerase target is HCV NS5B which is the viralRNA-dependent RNA polymerase (RdRp) that is responsible for viralreplications. HCV NS5B protein, is released from a polyprotein and isinvolved in the synthesis of double-stranded RNA from a single-strandedviral RNA genome. It is believed that the replication and/orreproduction of HCV virus may be inhibited or prevented through theinhibition of NS5B and suppress or prevent the formation of thedouble-stranded HCV RNA.

To demonstrate that the compounds of formula (I) act by specificinhibition of NS5B, the compounds may be tested for the lack ofinhibitory activity in an assay measuring the activity of anRNA-dependent RNA polymerase other than HCV polymerase or in a DNAdependent RNA polymerase assay.

Pharmaceutical Compositions

The invention also provides a pharmaceutical composition comprising acompound of formula (I) and a pharmaceutically acceptable carrier.

The pharmaceutical composition may further comprise or be administeredin combination with one or more other antiviral agents such as Ribavirin(Copegus® or Rebetol®), an antiviral nucleoside inhibitor of NS5Bpolymerase (such as4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-pyrrolo[2,1-f][1,2,4]triazine;PSI-7977; PSI-938; RG7128 or mericitabine; IDX-184; INX-189 and othersuch agents that may be developed), a non-nucleoside inhibitor of NS5Bpolymerase (such as GS-9190 or tegobuvir; PF-868554 or filibuvir;VX-222; IDX-375; ABT-072; ABT-333; ANA-598 or setrobuvir; BI207127;JTK-853; GS-9669; and other such agents that may be developed), a NS3/4aprotease inhibitor (such as telaprevir or Incivek®; boceprevir orVictrelis®; BI-201335; TMC-435; RG-7227 or danoprevir; MK-7009 orvaniprevir; GS-9451; GS-9256; BMS-650032; ACH-1625; ACH-2684; MK-5172;ABT-450; IDX-320; SCH-900518 and other such agents that may bedeveloped), an NS5A inhibitor (such as BMS-790052 (daclatasvir);GS-5885; ABT-267; PPI-461; ACH-2928; GSK2336805 and other such agentsthat may be developed) and/or inhibitor of viral entry, assembly oregress. The composition may also additionally comprise at least oneimmunomodulatory agent for example an interferon or interferonderivative such as interferon alpha 2B (such as Intron® A interferonavailable from Schering Corp., Kenilworth, N.J.), pegylated interferonalpha 2A (such as Pegasys® available from Hoffmann-LaRoche, Nutley,N.J.), pegylated interferon alpha 2B (such as Peg-Intron® available fromSchering Corp., Kenilworth, N.J.), consensus interferon (such asinterferon alphacon-1, or Infergen® available from ValeantPharmaceuticals, Costa Mesa, Calif.), interferon alpha 2A, recombinantinterferon alpha 2A (such as Roferon® available from Hoffmann-LaRoche,Nutley, N.J.), or lymphoblastoid interferon tau, and/or an inhibitor ofinosine-5′-monophosphate dehydrogenase (IMPDH) and other large or smallmolecules known to modulate host immune responses.

Accordingly, in one embodiment of the pharmaceutical composition, theother antiviral agent is Ribavarin optionally in combination withpeg-IFN.

In another embodiment, the other antiviral agent is an NS5B inhibitor,more particularly a nucleoside inhibitor such as the bicyclicnucleosides and nucleotides of the general formula described inWO2010/002877, for example,4-amino-7-(2-C′-methyl-β-D-ribofuranosyl)-pyrrolo[2,1-f][1,2,4]triazine.

In yet another embodiment, the other antiviral agent is an NS3/4Aprotease inhibitor such as telaprevir (VX-950) or Incivek®; bocepreviror Victrelis®; BI-201335; TMC-435; RG-7227 or danoprevir; MK-7009 orvaniprevir; GS-9451; GS-9256; BMS-650032; ACH-1625; ACH-2684; MK-5172;ABT-450; IDX-320; SCH-900518, particularly telaprevir (VX-950).

In still another embodiment, the other antiviral agent is an NS5Ainhibitor such as BMS-790052 (daclatasvir); GS-5885; ABT-267; PPI-461;ACH-2928; GSK2336805, particularly BMS-790052 (daclatasvir).

It will be understood that combined administration of the compounds ofthe invention with the other antiviral agent may be concurrent,sequential or separate administration.

The term “composition” is intended to include the formulation of anactive ingredient with conventional carriers and excipients, and alsowith encapsulating materials as the carrier, to give a capsule in whichthe active ingredient (with or without other carriers) is surrounded bythe encapsulation carrier. Any carrier must be “pharmaceuticallyacceptable” meaning that it is compatible with the other ingredients ofthe composition and is not deleterious to a subject. The compositions ofthe present invention may contain other therapeutic agents as describedabove, and may be formulated, for example, by employing conventionalsolid or liquid vehicles or diluents, as well as pharmaceuticaladditives of a type appropriate to the mode of desired administration(for example, excipients, binders, preservatives, stabilizers, flavours,etc.) according to techniques such as those well known in the art ofpharmaceutical formulation (See, for example, Remington: The Science andPractice of Pharmacy, 21st Ed., 2005, Lippincott Williams & Wilkins).

The pharmaceutical composition includes those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, or capsules filled with thesame, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use.

Such pharmaceutical compositions and unit dosage forms thereof maycomprise conventional ingredients in conventional proportions, with orwithout additional active compounds or principles, and such unit dosageforms may contain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispensable granules. Asolid carrier can be one or more substances which may also act asdiluents, flavouring agents, solubilisers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

Suitable carriers are magnesium carbonate, magnesium stearate, talc,sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The term “preparation” is intended to include theformulation of the active compound with encapsulating material ascarrier providing a capsule in which the active component, with orwithout carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used assolid forms suitable for oral administration. Liquid form preparationsinclude solutions, suspensions, and emulsions, for example, water orwater-propylene glycol solutions. For example, parenteral injectionliquid preparations can be formulated as solutions in aqueouspolyethylene glycol solution.

Sterile liquid form compositions include sterile solutions, suspensions,emulsions, syrups and elixirs. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable carrier, such as sterilewater, sterile organic solvent or a mixture of both.

The compositions according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Pharmaceutical forms suitable for injectable use include sterileinjectable solutions or dispersions, and sterile powders for theextemporaneous preparation of sterile injectable solutions. They shouldbe stable under the conditions of manufacture and storage and may bepreserved against oxidation and the contaminating action ofmicroorganisms such as bacteria or fungi.

The solvent or dispersion medium for the injectable solution ordispersion may contain any of the conventional solvent or carriersystems for the compounds, and may contain, for example, water, ethanol,polyol (for example, glycerol, propylene glycol and liquid polyethyleneglycol, and the like), suitable mixtures thereof, and vegetable oils.

Pharmaceutical forms suitable for injectable use may be delivered by anyappropriate route including intravenous, intramuscular, intracerebral,intrathecal, epidural injection or infusion.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousother ingredients such as these enumerated above, as required, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilised active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, preferredmethods of preparation are vacuum drying or freeze-drying of apreviously sterile-filtered solution of the active ingredient plus anyadditional desired ingredients.

When the active ingredients are suitably protected they may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or it may be enclosed in hard or soft shell gelatincapsule, or it may be compressed into tablets, or it may be incorporateddirectly with the food of the diet. For oral therapeutic administration,the active compound may be incorporated with excipients and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like.

The amount of active compound in therapeutically useful compositionsshould be sufficient that a suitable dosage will be obtained.

The tablets, troches, pills, capsules and the like may also contain thecomponents as listed hereafter: a binder such as gum, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such a sucrose, lactose or saccharin may be added or a flavouringagent such as peppermint, oil of wintergreen, or cherry flavouring. Whenthe dosage unit form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier.

Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit. For instance, tablets,pills, or capsules may be coated with shellac, sugar or both. A syrup orelixir may contain the active compound, sucrose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavouring such ascherry or orange flavour. Of course, any material used in preparing anydosage unit form should be pharmaceutically pure and substantiallynon-toxic in the amounts employed. In addition, the active compound (s)may be incorporated into sustained-release preparations andformulations, including those that allow specific delivery of the activepeptide to specific regions of the gut.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,or other well known suspending agents.

Pharmaceutically acceptable carriers and/or diluents include any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilising agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavoured base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension.

In the case of a spray, this may be achieved for example by means of ametering atomising spray pump. To improve nasal delivery and retentionthe compounds according to the invention may be encapsulated withcyclodextrins, or formulated with other agents expected to enhancedelivery and retention in the nasal mucosa.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas.

The aerosol may conveniently also contain a surfactant such as lecithin.The dose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g. gelatin, or blister packs from which thepowder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 5 to 10 microns or less.Such a particle size may be obtained by means known in the art, forexample by micronisation.

When desired, formulations adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

It is especially advantageous to formulate parenteral compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the subjects to be treated; each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms aredictated by and directly dependent on (a) the unique characteristics ofthe active material and the particular therapeutic effect to beachieved, and (b) the limitations inherent in the art of compoundingsuch an active material for the treatment of a HCV viral infection inliving subjects having a diseased condition in which bodily health isimpaired.

The invention also includes the compounds in the absence of carrierwhere the compounds are in unit dosage form.

Compositions comprising compounds of the invention formulated for oraldelivery either alone or in combination with another HCV antiviral agentare particularly preferred.

As such, in one embodiment there is provided a pharmaceuticalcomposition comprising a compound of formula (I) or salts, N-oxides,solvates, hydrates, racemates, enantiomers or diastereomers thereof, apharmaceutically acceptable carrier and optionally another HCV antiviralagent selected from the group consisting of Ribavarin, an NS5Binhibitor, an NS3/4A protease inhibitor and an NS5A inhibitor. In afurther embodiment the pharmaceutical composition may additionallycomprising at least one immunomodulatory agent such as peg-IFN. In stilla further particularly preferred embodiment, the pharmaceuticalcomposition is administered in an effective amount to a subject in needof treatment for a HCV infection.

Methods of Treatment

The compounds of formula (I) may be used in the treatment of aFlaviviridae viral infection such as a HCV infection.

Generally, the term “treatment” means affecting a subject, tissue orcell to obtain a desired pharmacological and/or physiological effect andincludes: (a) inhibiting the viral infection, i.e. arresting itsdevelopment or further development; (b) relieving or ameliorating theeffects of the viral infection, i.e. cause regression of the effects ofthe viral infection; (c) reducing the incidence or the viral infectionor (d) preventing the infection from occurring in a subject, tissue orcell predisposed to the viral infection disease or at risk thereof, buthas not yet been diagnosed with a protective pharmacological and/orphysiological effect so that the viral infection does not develop oroccur in the subject, tissue or cell.

The prevention of hepatitis C means, for example, administration of apharmaceutical agent to a subject found to carry a HCV by a test and thelike but without a symptom of infection, or to a subject who shows animproved disease state of hepatitis after a treatment of hepatitis C,but who still carries a HCV and is associated with a risk of recurrenceof hepatitis.

The term “subject” as used herein refers to any animal, in particularmammals such as humans having a disease or condition which requirestreatment with the compound of formula (I).

The term “administering” refers to providing the compound orpharmaceutical composition of the invention to a subject suffering fromor at risk of the diseases or conditions to be treated or prevented.

The term “viral infection” refers to the introduction of a virus intocells or tissues, e.g., hepatitis C virus (HCV). In general, theintroduction of a virus is also associated with replication. Viralinfection may be determined by measuring virus antibody titer in samplesof a biological fluid, such as blood, using, e.g., enzyme immunoassay.Other suitable diagnostic methods include molecular based techniques,such as RT-PCR, direct hybrid capture assay, nucleic acid sequence basedamplification, and the like. A virus may infect an organ, e.g., liver,and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease andhepatocellular carcinoma.

The term “Flaviviridae virus” refers to a virus of the familyFlaviviridae, which family includes the Hepacivirus Flavivirus andPestivirus or hepatitis C-like virus genera. A representative species ofthe genus of hepatitis C-like viruses is hepatitis C virus.

Dosages

The term “therapeutically effective amount” refers to the amount of thecompound of formula (I) that will elicit the biological or medicalresponse of a subject, tissue or cell that is being sought by theresearcher, veterinarian, medical doctor or other clinician.

In the prevention or treatment of HCV infections or diseases anappropriate dosage level will generally be about 0.01 to 500 mg per kgsubject body weight per day which can be administered in single ormultiple doses. Preferably, the dosage level will be about 0.1 to about250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.A suitable dosage level may be about 0.01 to 250 mg/kg per day, about0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within thisrange the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.The dosage may be selected, for example to any dose within any of theseranges, for therapeutic efficacy and/or symptomatic adjustment of thedosage to the subject to be treated.

It will be understood that the specific dose level and frequency ofdosage for any particular subject may be varied and will depend upon avariety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the age, body weight, general health, sex, diet, mode and time ofadministration, rate of excretion, drug combination, the severity of theparticular condition, and the subject undergoing therapy.

It will further be understood that when the compounds of the inventionare to be administered in combination with one or more HCV antiviralagents the dosage forms and levels may be formulated for eitherconcurrent, sequential or separate administration or a combinationthereof.

General Method(s)

Compounds of the invention may be generally prepared by the followinggeneral method(s).

Compounds of formula (I) may be generally synthesized via a syntheticintermediate of general formula (II) as previously described. Suitablecoupling conditions will be familiar to those skilled in the art andinclude, but are not limited to, alkylation and Mitsunobu, reactions.

It will be understood that unless otherwise defined each moiety having asubstitutable hydrogen such as for example, alkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, ineach occurrence as described in the general schemes and methods whichfollow may be optionally substituted.

It will also be understood that the particular examples which aredescribed herein may undergo further functionalisation using methodsknown in the art to form further examples of compounds of the invention.

General Method A

Synthesis of Intermediate (I)

Step a) The arylaldehyde was nitrated using a mixture of fuming nitricacid and sulfuric acid to give a mixture of mono-, di- and tri-nitratedproducts.

Step b) The mono-nitrohaloarylaldehyde was separated by conventionalseparation techniques (e.g. column chromatography) and again subjectedto the nitrating conditions described above to give the correspondingdinitroarylhaloarylaldehyde.

Step c) The dinitroarylhaoloaldehyde was reacted with a suitablysubstituted boronic acid or boronic acid derivative in the presence of asuitable catalyst (e.g. tetrakistriphenylphosphinepalladium(0)) and asuitable base (e.g. sodium carbonate) in a suitable solvent (e.g.toluene) as described by Miyaura and. Suzuki (see Miyaura, N.; Suzuki,A. J. Chem. Soc., Chem. Commun. 1979, 866-867) to give the correspondingdinitroaldehyde.Step d-i) The dinitroaldehyde was then reacted with a primary aryl- oralkylamine (e.g. 4-bromoaniline) in the presence of a cyanide source(e.g. sodium cyanide) and acetic acid and acetic anhydride to give thecorresponding nitrocyanoindazole-N-oxide where R₃ is an optionallysubstituted aryl or heteroaryl moiety. The nitrocyanoindazole-N-oxidecan be converted to the corresponding nitrocyanoindazole by treatmentwith a reagent such as phosphorus (III) trichloride.Step e-i) The cyano group of the nitrocyanoindazole can then behydrolysed to the corresponding nitroindazole carboxylic acid (e.g.using NaOH in aqueous EtOH)Step f-i) The nitroindazole carboxylic acid can then be coupled to anamine using standard peptide coupling conditions (e.g.HATU/DIPEA/acetonitrile) to give the nitroindazoleamide.Step d-ii) Alternatively, the dinitroaldehyde is treated with a suitablysubstituted primary arylamine (e.g. phenyl amine) heteroarylamine (e.g.pyridin-2-amine such as 5-C₁₋₃alkyl-pyridin-2-amine or5-halo-pyridin-2-amine) in a suitable solvent (e.g. EtOH) to give thecorresponding imine, which is then treated in the same reaction withtriphenylphosphine to give the corresponding nitroindazole.Step e-ii) The nitroindazole derived from step d-ii) was treated with asuitable halogenating reagent (e.g. N-bromosuccinimide) in a suitablesolvent (e.g. DMF) to give the corresponding halonitroindazole.Step f-ii) The halonitroindazole derived from step e-ii) was dissolvedin a suitable solvent (e.g. THF) and treated with a suitable primaryamine (e.g. methylamine) in the presence of a suitable catalyst (e.g.tetrakis(triphenylphosphine)palladium(0) and carbon monoxide to give, onwork-up, the corresponding nitroindazoleamide.Step g) The nitroindazoleamide can then be reduced to the correspondingnitroindazoleamine using standard conditions normally associated withthe reduction of an arylnitro-group to an aniline (e.g iron in thepresence of an aqueous alcoholic solvent).Step h) The amino analogue was first converted to the bis-sulfonylanalogue using standard sulfonylation conditions with an activatedsulfonic acid (e.g. methanesulfonyl chloride) and base (e.g. DIPEA) inan organic solvent (e.g. DCM). The bis-sulfonyl analogue then underwenthydrolysis using base (e.g. potassium hydroxide) in aqueous alcoholicsolvent (e.g. EtOH) to give the desired sulfonamide. Alternatively, theamino analogue was converted directly to the desired sulphonamide byreaction with the activated sulfonic acid (e.g. difluoromethanesulfonylchloride) in a basic organic solvent (e.g pyridine).Coupling ConditionsStep i) The compounds of general formula (I) may then be generallyprepared from Intermediate (I) i.e. compound of formula (II) aspreviously defined by: (i) coupling an optionally substitutedalkyl-halo/triflate/tosylate/mesylate moiety under alkylation conditionsi.e. the sulphonamide compound of formula (II) is dissolved/suspended ina suitable solvent (e.g. ACN) and treated with a suitable alkylmesylate, triflate, tosylate or halide in the presence of a suitablebase (e.g. potassium carbonate) to give, upon work-up, the correspondingalkylated sulphonamide of formula (I); or alternatively, (ii) coupling ahydroxylated precursor moiety under Mitsunobu reaction conditionswherein the sulphonamide compound of formula (II) and a suitablysubstituted primary or secondary alcohol in a suitable solvent (e.g.THF) is treated with triphenylphosphine and a suitable di-imide ordi-imide equivalent (e.g. DIAD) to give, upon work-up, the correspondingsubstituted sulphonamide of formula (I).

It will be understood that the precursor moieties i.e. of generalformula (III) as previously defined may contain an optionallysubstituted 4-membered heterocyclic ring or alternatively, theoptionally substituted 4-membered heterocyclic ring may be introducedinto a suitable precursor component e.g. a diol or alkene, of thecompound by undergoing further functionalisation using methods known inthe art.

Examples

Those skilled in the art will appreciate that the invention describedherein is susceptible to variations and modifications other than thosespecifically described. The invention will now be described withoutlimitation by reference to the non-limiting examples which follow.

Synthetic Methods

¹H NMR spectra were recorded on either a Brüker Avance DRX 400, AC 200or AM 300 spectrometer. Spectra were recorded in deuterated solvents(CDCl₃, MeOD, DMSO, CD₃CN, or Acetone) using the residual solvent peakas a reference. Chemical shifts are reported on the δ scale in parts permillion (ppm) using the following conventions to assign themultiplicity: s (singlet), d (doublet), t (triplet), q (quartet), p(pentet), m (multiplet) and prefixed br (broad). Mass spectra (ESI) wererecorded on either a Micromass Platform QMS or Thermo Finnigan LCQAdvantage spectrometer. Flash chromatography was performed on 40-63 μmsilica gel 60 (Merck No. 9385). Automated flash chromatography wasperformed either on a Combi-Flash™ purification system usingCombi-Flash™ silica gel columns or on a Biotage SP4 purification systemusing either GraceResolv™ silica gel cartridges, Grace Reveleris™ C-18reverse phase silica gel cartridges or Biotage SNAP™ C-18 reverse phasesilica gel cartridges. Preparative HPLC was carried out using either aGilson 322 pump with a Gilson 215 liquid handler and a HP1100 PDAdetector or an Agilent 1200 Series mass detected preparative LCMS usinga Varian XRs C-18 100×21.2 mm column. Unless otherwise specified, theHPLC systems employed Phenomenex C8(2) columns using either acetonitrileor acetonitrile containing 0.06% TFA in water, water containing 0.1% TFAor water containing 0.1% formic acid.

During the reactions a number of the moieties may need to be protected.Suitable protecting groups are well known in industry and have beendescribed in many references such as Protecting Groups in OrganicSynthesis, Greene T W, Wiley-Interscience, New York, 1981.

The abbreviations used in the Examples are as follows unless indicatedotherwise:

Ac: acetyl

ACN: acetonitrile

aq.: aqueous

conc.: concentrated

CV: column volume

d. day

dba: dibenzylideneacetone

DCM: dichloromethane

DIPEA: N,N-diisopropylethylamine

DMF: N,N-dimethylformamide

DMSO: dimethylsulfoxide

dppf: 1,1′-bis(diphenylphosphino)ferrocene

EtOAc: ethyl Acetate

EtOH: ethanol

ESI: electrospray ionisation

h: hour(s)

HATU: 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

HPLC: high performance liquid chromatography

LCMS: liquid chromatography coupled mass spectrometry

min: minute(s)

MeOH: methanol

MS: mass spectrometry

NBS: N-bromosuccinimide

NMR: nuclear magnetic resonance

PyBOP: benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate

s second(s)

SM: starting material

RT: room temperature

TEA: triethylamine

THF: tetrahydrofuran

TFA: trifluoroacetic acid

TLC: thin-layer chromatography

Compounds of Formula (II) Compound(s) of Formula (II) where R₃ is aSubstituted Aryl (Phenyl) Group2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide(1)

5-Bromo-2-nitrobenzaldehyde (ii)

To ice cold conc. sulphuric acid (400 mL) was added fuming nitric acid(200 mL) dropwise followed by 3-bromobenzaldehyde (i) (100 g, 0.540 mol)dropwise over 15 min. The reaction mixture was stirred for 10 min andthen poured carefully over ice-water. The resulting solids were filteredand then purified by flash column chromatography on silica gel, elutingwith EtOAc:n-hexane (gradient elution from 1% to 20% v/v) to give (ii)(60 g, 48%).

5-Bromo-2,4-dinitrobenzaldehyde (iii)

To ice cold conc. sulphuric acid (360 mL) was added fuming nitric acid(180 mL) dropwise followed by (ii) (60 g, 0.26 mol) dropwise over 15min. The reaction mixture was stirred for 10 min and then allowed towarm to RT. After 30 min, the reaction mixture was heated at 45° C. for2 h and then at 50° C. for 3 h and then allowed to cool to RT. Thereaction mixture was then poured carefully over ice-water and theorganics were extracted into chloroform (500 mL). The volatiles weredried (MgSO₄) and concentrated in vacuo. The residue was purified byflash column chromatography eluting with EtOAc:n-hexane (gradientelution from 5% to 30% v/v) to give (iii) (5.1 g, 7%).

5-Cyclopropyl-2,4-dinitrobenzaldehyde (iv)

To a stirred solution of (iii) (3 g, 10.9 mmol) in toluene (75 mL) wasadded a solution of sodium carbonate (2.29 g, 21.8 mmol) in water (15mL). The mixture was sparged with nitrogen for 10 min whereuponcyclopropyl boronic acid (1.4 g, 16.4 mmol) andtetrakis(triphenylphosphine) palladium(0) (0.25 g, 0.22 mmol) were addedand the reaction mixture was heated at reflux and progress monitored byTLC. After heating for 6 h the reaction was then cooled to RT anddiluted with EtOAc (100 mL). The organic layer was separated andconcentrated in vacuo. Purification of the residue by columnchromatography on silica gel to gave (iv) (2 g, 78%).

2-(4-Chlorophenyl)-5-cyclopropyl-6-nitro-2H-indazole-3-carbonitrile (v)

To a stirred suspension of (iv) (20 g, 0.09 mol) in acetic acid (400 mL)was added 4-chloroaniline (21.6 g, 0.17 mol) and the reaction heated at60° C. to obtain a complete solution. To this solution was added sodiumcyanide (20 g, 0.41 mol) portionwise over 20 min. The reaction mixturewas stirred for 5 min whereupon acetic anhydride (6 mL) was added. Uponthe formation of a precipitate, an additional quantity of sodium cyanide(20 g, 0.41 mol) was added portionwise. After stirring for 1 h, thereaction mixture was cooled to RT, diluted with MeOH (30 ml) and thesolids separated by filtration. The solid cake was dissolved inchloroform (400 ml) and the organics washed with water (2×100 ml), dried(MgSO₄) and concentrated in vacuo to give the intermediate2-(4-chlorophenyl)-5-cyclopropyl-6-nitro-2H-indazole-3-carbonitrile1-oxide (34.6 g). ESI-MS m/z calculated for [M+H]⁺: 355.1. found: 355.2.¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1H), 7.72-7.50 (m, 5H), 2.44-2.30 (m,1H), 1.18-1.05 (m, 2H), 0.85-0.71 (m, 2H).

To a stirred solution of the crude intermediate2-(4-chlorophenyl)-5-cyclopropyl-6-nitro-2H-indazole-3-carbonitrile1-oxide (23 g, 0.06 mmol) in chloroform (230 mL) was added phosphorustrichloride (23 mL) and the reaction mixture was then heated at 60° C.After 2 h, the reaction was cooled to RT and ice-water added (ca. 200mL). The organics were extracted into DCM (3×200 mL), dried (Na₂SO₄) andconcentrated in vacuo to give (v) (20.3 g, 92%), which was usedunpurified in subsequent steps. ESI-MS m/z calculated for [M+H]⁺: 339.1.found: 339.0. ¹H NMR (400 MHz, CDCl₃) δ 8.25 (s, 1H), 7.92-7.81 (m, 2H),7.69-7.57 (m, 3H), 2.42-2.29 (m, 1H), 1.14-1.03 (m, 2H), 0.82-0.72 (m,2H).

2-(4-Chlorophenyl)-5-cyclopropyl-6-nitro-2H-indazole-3-carboxylic acid(vi)

To a stirred solution of (v) (20 g, 0.06 mol) in EtOH:water (400 ml, 1:1v/v) was added NaOH (59.0 g, 0.02 mol) and the reaction mixture heatedat 90° C. for 15 h. The reaction was then cooled to RT and the volatileswere removed in vacuo. The residual aqueous solution was acidified to pH2 with aq. 2N HCl solution whereupon a solid precipitated from solution.The solid was separated by filtration and dissolved in EtOAc (300 mL),dried (Na₂SO₄) and concentrated in vacuo to give (vi) (7.5 g, withpurity 75% by HPLC analysis). The material was used unpurified insubsequent steps.

ESI-MS m/z calculated for [M+H]⁺: 358.0. found: 358.0. ¹H NMR (400 MHz,d₆-DMSO) δ 8.22 (s, 1H), 7.93 (s, 1H), 7.76-7.52 (m, 2H), 7.29-7.09 (m,2H), 2.39-2.19 (m, 1H), 1.05-0.93 (m, 2H), 0.73-0.65 (m, 2H).

(2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-nitro-2H-indazole-3-carboxamide(vii)

To a stirred solution of (vi) (15 g, unpurified from the previous step)in DMF (300 mL) was added DIPEA (27.7 mL, 0.16 mol), HATU (23.9 g, 0.06mol) and methylamine (2.0M solution in THF, 60 mL, 0.12 mol). Thereaction mixture was stirred for 2 h at RT and then poured onto the ice.The precipitate was then separated by filtration and the solid obtainedwas dissolved in DCM (300 mL), dried (Na₂SO₄) and the volatiles removedin vacuo to give (vii) (16.5 g with purity 86.5% by HPLC analysis),which was used unpurified in subsequent steps. ESI-MS m/z calculated for[M+H]⁺: 371.1. found: 371.0. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H),7.74 (s, 1H), 7.62-7.45 (m, 4H), 5.91 (brs, 1H), 3.09-2.97 (m, 3H),2.40-2.28 (m, 1H), 1.04-0.95 (m, 2H), 0.73-0.65 (m, 2H).

6-Amino-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide(viii)

To a solution of (vii) (127 mg, 0.34 mmol) in THF (2.5 mL) and MeOH (7.5mL) was added Raney nickel (20 mg) and the reaction stirred vigorouslyunder hydrogen atmosphere at 60° C. for 2 h. The reaction was dilutedwith MeOH (40 mL), filtered and then concentrated to dryness to give(viii) (97 mg, 83%). ESI-MS m/z calculated for [M+H]⁺: 341.1. found:341.0. ¹H NMR (400 MHz, d₆-DMSO) δ 7.58-7.47 (m, 4H), 7.23 (s, 1H), 6.64(m, 1H), 2.85-2.76 (m, 3H), 1.82-1.72 (m, 1H), 0.96-0.89 (m, 2H),0.64-0.55 (m, 2H).

2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide(1)

To a stirred solution of (viii) (3.0 g, 8.8 mmol) in DCM (90 ml) wasadded DIPEA (5.4 mL, 30.8 mmol.) and the reaction mixture cooled to 0°C. Methanesulfonyl chloride (1.70 mL, 22.0 mmol) was added dropwise andthe reaction stirred for 2 h. Water (100 mL) was then added to thereaction and pH of the aqueous layer adjusted to pH˜5 using aq. 2N HCl.The organics were separated and the aqueous layer was extracted intoEtOAc (2×100 mL). The combined organics were dried (Na₂SO₄) andconcentrated in vacuo. A portion of the solid obtained (2.6 g) wasdissolved in EtOH (166 mL), solid potassium hydroxide (2.82 g, 50.3mmol) was added and the reaction heated at 50° C. After 2 h, thereaction mixture was cooled to RT, diluted with water (100 mL) and thepH adjusted to 5 using aq. 2N HCl. The organics were extracted intoEtOAc (3×100 mL), dried (Na₂SO₄) and concentrated in vacuo to give 4 gcrude of the desired product. A portion of the crude material (1 g) waspurified by column chromatography on silica gel eluting withEtOAc:n-hexane (gradient elution from 10% to 40% v/v) to give Compound(1) (330 mg). ESI-MS m/z calculated for [M+H]⁺: 419.1. found: 419.1. ¹HNMR (400 MHz, d₆-Acetone) δ 7.79 (brs, 1H), 7.66 (s, 1H), 7.61 (brs,1H), 7.56-7.51 (m, 2H), 7.49 (s, 1H), 7.46-7.41 (m, 2H), 3.02 (s, 3H),2.81 (d, J=4.7 Hz, 3H), 2.11-2.01 (m, 1H), 0.96-0.90 (m, 2H), 0.66-0.59(m, 2H).

Compound(s) of Formula (II) where R₃ is a Substituted Heteroaryl(Preferably 6-Membered and Containing at Least One Nitrogen Atom) Group5-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide(2)

5-Cyclopropyl-2-(5-methylpyridin-2-yl)-6-nitro-2H-indazole (ii)

To a stirred solution of 5-cyclopropyl-2,4-dinitrobenzaldehyde (preparedaccording to the synthesis of Compound (1)) (50 mg, 0.212 mmol) in EtOH(750 mL) was added 5-methylpyridin-2-amine (25 mg, 0.23 mmol) and theresultant solution stirred at RT for 2 d after which time a solid hadprecipitated from solution. Triphenylphosphine (167 mg, 0.64 mmol) wasadded in a single portion and the reaction then heated at 100° C. in asealed tube for 4 h. Upon cooling to RT, the reaction was diluted withDCM (2 mL) and the organics were washed with aq. 30% hydrogen peroxidesolution (2 mL). The organics were separated and filtered through a plugof MgSO₄ and then purified by automated column chromatography (BiotageSP4, Grace 4 g silica cartridge) eluting with EtOAc:n-heptane (gradientelution, 0% equil. (2 CV), 0% (1 CV), 0 to 100% (35 CV), 100% (5 CV)) togive (ii) (27 mg, 43%). ESI-MS: calculated [M+H]⁺ 295.1, observed [M+H]⁺295.2.

3-Bromo-5-cyclopropyl-2-(5-methylpyridin-2-yl)-6-nitro-2H-indazole (iii)

To a solution of (ii) (1.08 g, 3.67 mmol) in DMF (15 mL) was addedN-bromosuccinimide (780 mg, 4.40 mmol) and the resulting mixture stirredat 80° C. for 1.5 h. The reaction mixture was then cooled to RT and thesolvent was removed under reduced pressure. The residue was dissolved inEtOAc (100 mL) and washed with aq. saturated sodium bicarbonate (20 mL)and brine (20 mL). The organic phase was dried (MgSO₄) and the volatilesremoved in vacuo to give (iii) (1.37 g, >99%). ESI-MS: calculated [M+H]⁺373.0/375.0, observed [M+H]⁺ 373.1/375.1.

5-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-nitro-2H-indazole-3-carboxamide(iv)

Compound (iii) (5.80 g, 16.0 mmol), methylamine (2M solution in THF, 120mL, 230 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.00 g, 1.73mmol) were placed in a medium pressure reaction vessel. The mixture wasdegassed and purged with carbon monoxide gas several times and thenstirred at 70° C. under 40 psi of CO (g) for 1.5 hr. After cooling toRT, the resulting suspension was filtered and washed with EtOAc. Thesolid was set aside and the filtrate was concentrated under reducedpressure. The residue was triturated with EtOAc and the solids separatedby filtration. The combined solids were dried in vacuo to give (iv)(6.00 g, >100%), which was used in subsequent steps withoutpurification. ESI-MS: calculated [M+H]⁺ 352.1, observed [M+H]⁺ 352.1.

6-Amino-5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide(v)

To a suspension of (iv) (5.6 g, 16.0 mmol) in EtOH (150 mL) and water(30 mL) was added ammonium chloride (6.25 g, 112.8 mmol) followed byiron powder (6.00 g, 112 mmol). The mixture was heated to 80° C. andstirred for 1.5 h whereupon the reaction mixture was filtered throughcelite, washed with MeOH (50 mL) and the combined filtrate thenconcentrated in vacuo. The residue was suspended in water and the solidseparated by filtration. The residual solid was dried in vacuo at 50° C.for 12 h to give (v) (2.75 g, 53% over 2 steps from (iii)). ESI-MS:calculated [M+H]⁺ 322.2 observed [M+H]⁺ 322.2.

5-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide(2)

To a suspension of (v) (2.75 g, 8.6 mmol) in DCM (30 mL) at 0° C. wasadded DIPEA (4.40 mL, 25.0 mmol) followed by methanesulfonyl chloride(3.30 mL, 42.0 mmol). The reaction mixture was stirred at RT for 1 h andthen washed with aq. sat'd. NaHCO₃ (50 mL), brine (50 mL) and dried(MgSO₄). Removal of solvent in vacuo gave the crude product, which wasthen dissolved in EtOH (100 mL) and 1,4-dioxane (20 mL). To theresultant solution was added KOH (˜10 eq) portionwise at RT until the pH8-9 was achieved. The reaction mixture was then slowly neutralised byaddition of 1M HCl (aq) and volatiles removed in vacuo. The residue wastaken up in EtOAc (50 mL) and washed with water (50 mL). The organicphase was dried (MgSO₄), concentrated in vacuo and the solid residuethen triturated with EtOAc. The solid was separated by filtration anddried in a stream of air and purified further by automated columnchromatography (Biotage SP4, 12 g Grace Resolve cartridge) eluting withEtOAc:n-heptane (gradient elution from 60% to 100%.v/v) to give Compound(2) (2.42 g, 72%). ESI-MS: calculated [M+H]⁺ 400.1 observed [M+H]⁺400.1. ¹H NMR (400 MHz, CDCl₃) δ 8.94 (brd, J=3.9 Hz, 1H), 8.38 (s, 1H),7.99 (s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.86-7.77 (m, 2H), 7.17 (s, 1H),3.18 (s, 3H), 3.09 (d, J=4.7 Hz, 3H), 2.50 (s, 3H), 1.84-1.76 (m, 1H),1.15-1.04 (m, 2H), 0.84-0.74 (m, 2H).

Compounds of Formula (III) for Coupling to Compounds of Formula (II)

An extensive selection of suitable compounds of formula (III) forcoupling to compounds of formula (II) under suitable conditions,particularly alkylation and Mitsunobu conditions, are available fromcommercial suppliers or will be familiar to those in the art. A furtherdiversity of compounds of formula (III) however may be preparedaccording to one or more of the following methods.

Step a) A suitably substituted alkylphosphonate is treated with asuitable base (e.g. potassium tert-butoxide) in a suitable solvent (e.g.THF) to give the corresponding phosphonium ylide. A substituted cyclicketone can be added to the resultant ylide to form, on work-up, thecorresponding α,β-unsaturated ester.Step b) The α,β-unsaturated ester derived from step a) can be reduced tothe corresponding alkyl ester using standard hydrogenation conditionssuch as hydrogen gas in the presence of a suitable catalyst (e.g. 10%palladium on carbon) and a suitable solvent (e.g. ethanol).Step c) The ester derived from step b) can be reduced to thecorresponding alcohol using a suitable reducing agent (e.g. lithiumborohydride) in a suitable solvent (e.g. diethyl ether).

2-(oxetan-3-yl)propan-1-ol

Ethyl 2-(oxetan-3-ylidene)propanoate (i)

To a solution of triethyl 2-phosphonopropionate (800 mg, 3.4 mmol) inanhydrous THF (3 mL) was added potassium tert-butoxide (340 mg, 3.1mmol). The reaction was stirred for 1 h at RT then oxetan-3-one (CAS-RN6704-31-0, available from commercial suppliers, 220 mg, 3.1 mmol) wasadded in a single portion. The reaction was heated at reflux for 20 hthen cooled to RT and adsorbed onto silica gel. Purification byautomated column chromatography (Biotage SP4) on silica gel (12 g Gracecartridges) eluting with EtOAc: n-heptane (gradient elution, 0% (equil.,5 CV), 0% (5 CV) 0-100% (25 CV), 100% (10 CV)) afforded (i) (151 mg,31%).

¹H NMR (400 MHz, CDCl₃) δ 5.44-5.37 (m, 2H), 5.30-5.23 (m, 2H), 4.17 (q,J=7.2 Hz, 2H), 1.68 (quint, J=1.8 Hz, 3H), 1.27 (t, J=7.2 Hz, 3H).

Ethyl 2-(oxetan-3-yl)propanoate (ii)

To a solution of (i) (151 mg, 0.97 mmol) in EtOH (54 mL) was added 10%Pd/C (50 mg, 0.05 mmol). The reaction was degassed and purged withhydrogen at balloon pressure (×3) then stirred under hydrogen at RT for16 h. The reaction mixture was filtered and the residue washed withacetonitrile (10 mL). The combined organics were concentrated in vacuoand the residue, (ii) (148 mg), was used without further purification.

2-(Oxetan-3-yl)propan-1-ol

To a suspension of lithium borohydride (40 mg, 1.87 mmol) in anhydrousEt₂O (2.5 mL) at 0° C. was added to a solution of crude (ii) (148 mg,0.94 mmol) in anhydrous Et₂O (2.5 mL). The reaction was warmed to RT andstirred for 18 h. Water (15 mL) was added cautiously to quench thereaction and the organics were extracted into EtOAc (3×15 mL), dried(MgSO₄) and concentrated in vacuo (without heating) to give2-(oxetan-3-yl)propan-1-ol (105 mg, 97%). ¹H NMR (400 MHz, CDCl₃) δ4.80-4.70 (m, 2H), 4.55 (dt, J=20.0 and 6.4 Hz, 2H), 3.46 (brt, J=4.6Hz, 2H), 2.98-2.84 (m, 1H), 2.14-2.00 (m, 1H), 0.87 (d, J=6.8 Hz, 3H).

Compounds of Formula (I) Alkylation of Compounds of Formula (II) toObtain Compounds of Formula (I)5-Cyclopropyl-N-methyl-2-(4-methylphenyl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide(3)

To a stirred solution of 2-(oxetan-3-yl)ethyl methanesulfonate (11 mg,0.06 mmol, prepared by treating 2-(oxetan-3-yl)ethanol withmethanesulfonyl chloride in DCM in the presence of DIPEA) was added5-cyclopropyl-6-(methanesulfonamido)-N-methyl-2-(p-tolyl)indazole-3-carboxamide(24 mg, 0.06 mmol) followed by potassium carbonate (68 mg, 0.49 mmol).The resultant suspension was heated at 60° C. for 18 h whereupon anotherportion of (oxetan-3-yl)ethyl methanesulfonate (81 mg, 0.45 mmol) in ACN(2 mL) was added and heating/stirring continued. After 24 h, thereaction mixture was diluted with EtOAc (15 mL) and the organics washedwith water (20 mL). The aqueous layer was back-extracted into EtOAc (15mL) and the combined organics were then washed with brine (10 mL), dried(MgSO₄) and the volatiles removed in vacuo. The residue was purified bypreparative HPLC eluting with ACN:0.1% formic acid in water (gradientelution, 5% to 30% to 40% to 100%) to give Compound (3) (4 mg, 14%).ESI-MS m/z calculated for [M+H]⁺: 483.2 found: 483.1. ¹H NMR (400 MHz,CD₃CN) δ 7.78 (s, 1H), 7.58 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.40 (d,J=7.94 Hz, 2H), 5.63 (brs, 1H), 4.86-4.78 (m, 2H), 4.40-4.33 (m, 2H),3.70 (t, J=7.94 Hz, 2H), 3.18-3.05 (m, 4H), 2.98 (d, J=5.0 Hz, 3H), 2.51(s, 3H), 2.47-2.38 (m, 1H), 2.17-1.97 (m, 2H), 1.19-1.03 (m, 3H),0.72-0.63 (m, 1H).

Step a) The alkene was converted to the corresponding epoxide usingstandard epoxidation conditions (e.g. treatment with N-bromosuccinimidefollowed by aq. NaOH) in a suitable solvent(s) (e.g. 1,4-dioxane andacetic acid). The resultant epoxide can be isolated and purified or usedcrude in subsequent procedures.Step b) Trimethylsulfoxonium iodide dissolved in a suitable solvent(e.g. tert-butanol) and treated with a suitable base (e.g. potassiumtert-butoxide). To the resultant ylide was added the epoxide derivedfrom step a) to give the resultant substituted oxetane.

2-(4-Chlorophenyl)-5-cyclopropyl)-N-methyl-6-{(methylsulfonyl)[3-(oxetan-2-yl)propyl]amino}-2H-indazole-3-carboxamide(4)

2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)(pent-4-en-1-yl)amino]-2H-indazole-3-carboxamide(i)

Synthesized under alkylation conditions by reacting2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide(200 mg, 0.48 mmol) with 4-penten-1-ol (0.1 mL). Work up andpurification afforded (i) (161 mg, 69%). ¹H NMR (400 MHz, CDCl₃) δ 7.72(d, J=0.5 Hz, 1H), 7.56-7.48 (m, 4H), 7.37 (s, 1H), 5.88-5.66 (m, 2H),5.03-4.93 (m, 2H), 3.73 (t, J=7.8 Hz, 2H), 3.05 (s, 3H), 3.01 (d, J=4.9Hz, 3H), 2.49-2.37 (m, 1H), 2.15-2.05 (m, 2H), 1.85-1.62 (m, 2H),1.15-1.04 (m, 2H), 1.04-0.93 (m, 1H), 0.67-0.52 (m, 1H). ESI-MS m/zcalculated for [M+H]⁺: 487.2. found: 487.1.

2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)[3-(oxiran-2-yl)propyl]amino}-2H-indazole-3-carboxamide(ii)

To a solution of (i) (156 mg, 0.32 mmol) and acetic acid (37 μL, 0.64mmol) in anhydrous 1,4-dioxane (15 mL) and water (20 mL) at 0° C. wasadded NBS (68 mg, 0.13 mmol) in a single portion. The reaction mixturewas allowed to warm slowly to room temperature over 1 h 25 min whereuponaq. 1 M NaOH solution (3 mL) was added and the reaction followed LCMSanalysis. After 30 min, the reaction mixture was diluted with water (10mL), extracted with EtOAc (3×10 mL) and the combined organics then dried(MgSO₄) and concentrated in vacuo to obtain (ii) (191 mg, >100%). Thecrude product was used without further purification in the next step.ESI-MS m/z calculated for [M+H]⁺ 503.2. found: 503.1.

2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)[3-(oxetan-2-yl)propyl]amino}-2H-indazole-3-carboxamide(iii)

An oven-dried flask was charged with a mixture of potassiumtert-butoxide (426 mg, 3.8 mmol) and trimethylsulfoxonium iodide (860mg, 3.9 mmol) in anhydrous tert-butanol (7.5 mL) under argon. Thereaction mixture was stirred vigorously at 50° C. for 5 h under argonthen added to a stirred solution of crude (ii) (191 mg) in anhydroustert-butanol (2.5 mL) in a single portion. The reaction was stirred at50° C. overnight under argon, cooled to RT and concentrated in vacuo.The residue was then partitioned between water (50 mL) and EtOAc (50 mL)and the organics separated. The aqueous layer was extracted aq withEtOAc (2×50 mL) and the combined organic layers dried (MgSO₄) andconcentrated in vacuo. The residue was dissolved in DMSO (2.5 mL) andthe mixture centrifuged. The supernatant solution was collected andsubjected to preparative HPLC (0.1% formic acid in acetonitrile: 0.1%formic acid in water, gradient elution 0% to 45% to 60% to 100%) to giveCompound (4) (31 mg, 16% over 2 steps). ¹H NMR (400 MHz, CD₃CN) δ 7.80(s, 1H), 7.60-7.50 (m, 4H), 7.35 (s, 1H), 6.98 (br s, 1H), 4.75-4.64 (m,1H), 4.55-4.46 (m, 1H), 4.39-4.31 (m, 1H), 3.78-3.69 (m, 2H), 3.07 (s,3H), 2.89 (d, J=4.8 Hz, 3H), 2.64-2.53 (m, 1H), 2.42-2.32 (m, 1H),2.31-2.19 (m, 1H), 1.81-1.49 (m, 3H), 1.09-0.97 (m, 3H), 0.67-0.58 (m,1H). ESI-MS m/z calculated for [M+H]⁺: 517.2. found: 517.0; m/zcalculated for [M+Na]⁺: 539.2. found: 539.1.

Mitsunobu Coupling of Compounds of Formula (II) and (III) to ObtainCompounds of Formula (I)5-Cyclopropyl-N-methyl-2-(5-methylpyrimidin-2-yl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide(5)

To a stirred suspension of5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide(i) (11 mg, 0.03 mmol) and 2-(oxetan-3-yl)ethanol (5.6 mg, 0.06 mmol) inTHF (200 μL) was added triphenylphosphine (11 mg, 0.04 mmol) followed byDIAD (8 μL, 0.04 mmol). The suspension dissolved slowly upon stirring.LCMS analysis of the reaction after 2.5 hr showed the presence ofstarting material and further aliquots of triphenylphosphine (5.0 mg,0.05 mmol) and DIAD (8 μL, 0.04 mmol) were added. After stirring for 2h, the reaction was diluted with EtOAc (10 mL), the organics washed withwater (10 mL), brine (10 mL) and dried (MgSO₄). The organics wereconcentrated in vacuo and the residue purified by automated columnchromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge)eluting with acetic acid: DCM (10% v/v, 10 CV) to remove thetriphenylphosphine oxide followed by MeOH: DCM (gradient elution, 0% to20%, 20 CV) to give Compound (5) (7.8 mg, 59%). ESI-MS m/z calculatedfor [M+H]⁺: 484.2. found: 484.2. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (brs,1H), 8.36 (s, 1H), 7.83-7.76 (m, 2H), 7.72 (s, 1H), 7.60 (s, 1H),4.84-4.71 (m, 2H), 4.34 (q, J=6.0 Hz, 2H), 3.74-3.56 (m, 2H), 3.10-2.99(m, 7H), 2.47 (s, 3H), 2.30 (ddd, J=13.6, 8.3, 5.4 Hz, 1H), 2.07-1.95(m, 2H), 1.09-0.94 (m, 3H), 0.65-0.56 (m, 1H).

Step a) The protected azetidine is converted to the correspondingdeprotected azetidine using standard conditions (for a list ofprotecting groups and conditions for their removal, see Greene, T. W.,Wiley-Interscience, New York, 1981).Step) The azetidine derived from step a) is then dissolved in a suitablesolvent (e.g. MeOH) and treated with an alkyl/aryl aldehyde or ketone(e.g. paraformaldehyde) in the presence of a reducing agent (e.g. sodiumborohydride) to give, upon work-up, the corresponding alkylatedazetidine. Alternatively, the azetidine from step a) can be N-alkylatedwith a suitably substituted alkyl halide, alkyl mesylate, alkyl tosylateor alkyl triflate using the alkylation conditions previously described.

6-{[2-(Azetidin-3-yl)ethyl](methylsulfonyl)amino}-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide(6)

To a solution of tert-butyl3-(2-{[2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)-2H-indazol-6-yl](methylsulfonyl)amino}ethyl)azetidine-1-carboxylate(prepared by reacting2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamidewith tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate), (25 mg, 0.04mmol) in DCM (3 mL) was added TFA (1 mL) and the reaction stirred atambient temperature. After 1 h, the reaction was concentrated in vacuoand the residue partitioned between EtOAc (25 mL) and aq. saturatedsodium bicarbonate (15 mL). The organic layer was separated and theaqueous layer extracted with EtOAc (3×15 mL). The combined organics werewashed with brine (15 mL), dried (MgSO₄), concentrated in vacuo andpurified by preparative HPLC eluting with acetonitrile:0.1% formic acidin water to afford Compound (6) (8.8 mg, 42%). ESI-MS m/z calculated for[M+H]⁺: 502.2. found: 502.1 ¹H NMR (400 MHz, CD₃CN) δ 8.40 (s, 1H), 7.83(s, 1H), 7.64-7.54 (m, 4H), 7.39 (s, 1H), 7.37 (br d, J=3.9 Hz, 1H),3.94-3.81 (m, 2H), 3.76-3.59 (m, 2H), 3.59-3.50 (m, 2H), 3.09 (d, J=10.3Hz, 3H), 2.97-2.86 (m, 4H), 2.43-2.33 (m, 1H), 1.95-1.86 (m, 2H),1.14-1.00 (m, 3H), 0.71-0.59 (m, 1H).

Post-Coupling Functionalisation (N-Alkylation by Reductive Amination)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{[2-(1-methylazetidin-3-yl)ethyl](methylsulfonyl)amino}-2H-indazole-3-carboxamide(7)

To a solution of Compound (6) (27 mg, 0.05 mmol) in MeOH (2 mL) wasadded, simultaneously, paraformaldehyde (30 mg) and sodium borohydride(30 mg). After 16 h at ambient temperature water (25 ml) was added andthe aqueous layer was extracted into EtOAc (3×30 mL). The combinedorganics were washed with brine (25 mL), dried (MgSO₄) and concentratedin vacuo to give a colourless oil (32 mg). The crude material waspurified by reverse phase preparative LCMS: Acetonitrile/water (0.1%formic acid) to give Compound (7) (7.70 mg, 30%). ESI-MS m/z calculatedfor [M+H]⁺: 516.2. found: 516.1. ¹H NMR (400 MHz, CD₃CN, formate salt) δ8.30 (s, 1H), 7.79 (s, 1H), 7.62-7.49 (m, 4H), 7.35 (s, 1H), 7.22 (br s,1H), 3.84-3.70 (m, 2H), 3.70-3.56 (m, 2H), 3.38 (dd, J=16.0, 7.5 Hz,2H), 3.07 (s, 3H), 2.89 (d, J=4.8 Hz, 3H), 2.75 (dt, J=15.4, 7.8 Hz,1H), 2.51 (s, 3H), 2.35 (ddd, J=13.6, 8.1, 5.6 Hz, 1H), 1.87 (ddd,J=17.6, 11.0, 5.2 Hz, 2H), 1.11-0.98 (m, 3H), 0.65-0.57 (m, 1H).

Post-Coupling Functionalisation (N-Acylation)6-{[2-(1-acetylazetidin-3-yl)ethyl](methylsulfonyl)amino}-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide(8)

To a solution of Compound (6) (8 mg, 0.02 mmol) in DCM (2.0 mL) wasadded acetic anhydride (0.1 mL) and pyridine (0.1 mL) and the mixturewas stirred at ambient temperature for 16 h. The reaction mixture wasthen concentrated in vacuo and the residue partitioned between EtOAc (25mL) and water (15 mL). The organic layer was separated and the aqueouslayer was extracted with EtOAc (3×15 mL). The combined organics werewashed with brine (15 mL), dried (MgSO₄) and concentrated in vacuo (32mg). The crude material was purified by reverse phase preparative LCMS:Acetonitrile/water (0.1% formic acid) to give Compound (8) (2.14 mg,20%). ESI-MS m/z calculated for [M+H]⁺: 544.2. found: 544.1. ¹H NMR (400MHz, CD₃CN) δ 7.85 (s, 1H), 7.63-7.54 (m, 4H), 7.40 (s, 1H), 7.05 (br s,1H), 4.21-4.14 (m, 1H), 3.93 (td, J=8.9, 3.2 Hz, 1H), 3.76-3.67 (m, 3H),3.49-3.43 (m, 1H), 3.11 (d, J=1.0 Hz, 3H), 2.93 (d, J=4.8 Hz, 3H),2.77-2.64 (m, 1H), 2.46-2.36 (m, 1H), 1.95-1.81 (m, 2H), 1.73 (d, J=2.4Hz, 3H), 1.14-1.02 (m, 3H), 0.69-0.58 (m, 1H).

Step a) The diol, formed by coupling a suitable triol precursor to asulphonamide of formula (II) under Mitsunobu conditions, was dissolvedin a suitable solvent (e.g. THF) and treated with a suitable base (e.g.potassium tert-butoxide) followed by p-toluenesulfonyl chloride to give,upon work-up, the corresponding oxetane.

2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-[{2[-2-methyloxetan-3-yl]ethyl}(methylsulfonyl)amino]-2H-indazole-3-carboxamide(9)

2-(4-Chlorophenyl)-5-cyclopropyl-6-{[4-hydroxy-3-(hydroxymethyl)pentyl](methylsulfonyl)amino}-N-methyl-2H-indazole-3-carboxamidewas prepared by alkylating2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide(i) with (±)-3-(hydroxymethyl)pentane-1,4-diol (prepared from(±)-3-acetyldihydrofuran-2(3H)-one as described by T. Mitsuhiro,Yanagihara, Hiroko and Y. Sachiko, Heterocycles, 1992 33, 489-492).Then, to a solution of Compound (i) (240 mg, 0.45 mmol) in anhydrous THF(35 mL) at 0° C. under argon was added potassium tert-butoxide (60 mg,0.53 mmol) in several portions (the reaction mixture became yellow incolour) followed by a solution of p-toluenesulfonyl chloride (95 mg,0.50 mmol) in anhydrous THF (10 mL), which was added dropwise over 10min. The reaction was warmed to RT and monitored by TLC/LCMS and thencooled to at 0° C. whereupon more potassium tert-butoxide (80 mg, 0.71mmol) was added. The reaction mixture was then warmed to RT and stirredfor 17 h after which time, aq. saturated ammonium chloride solution wasadded (20 mL) and the organics extracted into Et₂O (3×100 mL), dried(MgSO₄) and concentrated in vacuo. Purification by automated columnchromatography (Biotage SP4, Reveleris 4 g, silica gel cartridge)eluting with EtOAc:n-heptane (gradient elution, 50% to 100% v/v) andthen again by automated column chromatography (Biotage SP4, SNAPKP-C18-HS 30 g, reverse phase) eluting with ACN:water (gradient elution,0-100% v/v) gave Compound (9) as the trans isomer (mixture ofenantiomeric compounds (32) and (33)) (99 mg, 43%). ¹H NMR (400 MHz,CDCl₃) δ 7.70 (s, 1H), 7.56-7.48 (m, 4H), 7.37 (s, 1H), 5.88-5.82 (m,1H), 4.62-4.47 (m, 2H), 4.24-4.15 (m, 1H), 3.62 (t, J=7.9 Hz, 2H), 3.04(s, 3H), 2.99 (d, J=4.9 Hz, 3H), 2.67-2.53 (m, 1H), 2.45-2.33 (m, 1H),2.06-1.82 (m, 2H), 1.39 (d, J=6.1 Hz, 1.5H), 1.36 (d, J=6.1 Hz, 1.5H),1.17-1.04 (m, 2H), 1.04-0.93 (m, 1H), 0.66-0.54 (m, 1H). ESI-MS m/zcalculated for [M+H]⁺: 517.2. found: 517.0.

2-(4-chlorophenyl)-5-cyclopropyl-6-[2-(3-hydroxyazetidin-1-yl)ethyl-methylsulfonyl-amino]-N-methyl-indazole-3-carboxamide(22)

To a stirred solution of6-[2-bromoethyl(methylsulfonyl)amino]-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-indazole-3-carboxamide(5 mg, 0.01 mmol) in MeCN (500 uL) was added azetidin-3-ol hydrochloride(6.6 mg, 0.06 mmol) followed by potassium carbonate (6 mg). Theresultant suspension was heated at 65 deg C. in a sealed vial and after3 days, cooled to RT then filtered through a cotton wool plug. Theresidue was washed with MeCN (2 mL) and the volatiles removed in vacuo.The residual colourless oil was purified by preparative HPLC/MS(MeCN/0.1% formic acid in water (v/v)-gradient elution) to give Compound(22) as a white amorphous solid (4.5 mg, 91%). ¹H NMR (400 MHz, CD₃CN) δ7.90 (s, 1H), 7.63-7.53 (m, 4H), 7.42 (s, 1H), 7.03 (br s, 1H),4.67-4.40 (m, 2H), 4.17 (br s, 2H), 3.96 (br s, 2H), 3.80 (br s, 1H),3.38 (br s, J=41.2 Hz, 2H), 3.16 (s, 3H), 2.91 (d, J=4.8 Hz, 3H),2.34-2.33 (m, 1H), 1.18-1.01 (m, 3H), 0.68-0.58 (m, 1H). ESI-MS m/zcalculated for [M+H]⁺: 518.16. found: 518.10.

The following compounds were similarly prepared by reference to thegeneral method(s) and/or examples previously described.

TABLE 1 Compounds and characterisation data Observed LCMS m/z No [M +H]⁺ ¹H NMR 10 503.0. (400 MHz, CD₃CN) δ 7.81 (s, 1H), 7.61-7.50 (m, 4H),7.36 (s, 1H), 6.98 (br s, 1H), 4.71-4.61 (m, 2H), 4.30-4.19 (m, 2H),3.67-3.59 (m, 2H), 3.13-2.99 (m, 4H), 2.89 (d, J = 4.8 Hz, 3H),2.43-2.31 (m, 1H), 2.02-1.85 (m, 2H), 1.11-0.97 (m, 3H), 0.66-0.56 (m,1H). 11 517.0. (400 MHz, CD₃CN) δ 7.83 (d, J = 0.5 Hz, 1H), 7.61-7.50(m, 4H), 7.38 (s, 1H), 7.03-6.93 (m, 1H), 4.31-4.18 (m, 4H), 3.81-3.61(m, 2H), 3.09 (s, 3H), 2.89 (d, J = 4.8 Hz, 3H), 2.43-2.32 (m, 1H),2.07-1.86 (m, 2H), 1.24 (s, 3H), 1.12-0.97 (m, 3H), 0.66-0.56 (m, 1H).12 503.1. (400 MHz, CD₃CN) δ 7.91-7.86 (m, 1H), 7.60-7.48 (m, 4H), 7.27(s, 1H), 6.98 (s, 1H), 4.27 (d, J = 6.0 Hz, 1H), 4.21-4.12 (m, 4H),4.04-3.98 (m, 1H), 3.07 (s, 3H), 2.89 (d, J = 4.8 Hz, 3H), 2.41 (tt, J =8.1, 5.5 Hz, 1H), 1.36 (s, 3H), 1.16-1.01 (m, 3H), 0.69-0.60 (m, 1H). 13503.0. (400 MHz, CD₃CN) δ 7.86 (d, J = 5.5 Hz, 1H), 7.65-7.54 (m, 4H),7.40 (s, 1H), 7.02 (br s, 1H), 4.94-4.79 (m, 1H), 4.63-4.53 (m, 1H),4.49-4.38 (m, 1H), 3.89-3.70 (m, 2H), 3.12 (s, 3H), 2.93 (d, J = 4.8 Hz,3H), 2.73-2.61 (m, 1H), 2.46-2.28 (m, 2H), 2.10-1.84 (m, 2H), 1.16-1.01(m, 3H), 0.70-0.59 (m, 1H). 14 489.0. (400 MHz, CD₃CN) δ 7.79 (d, J =0.6 Hz, 1H), 7.59-7.51 (m, 4H), 7.31 (s, 1H), 6.97 (s, 1H), 4.63 (dd, J= 7.5, 6.2 Hz, 1H), 4.56 (dd, J = 7.7, 6.3 Hz, 1H), 4.31 (t, J = 6.0 Hz,1H), 4.22-4.12 (m, 2H), 3.98 (dd, J = 13.6, 6.3 Hz, 1H), 3.22-3.05 (m,4H), 2.89 (d, J = 4.8 Hz, 3H), 2.32-2.20 (m, 1H), 1.13-0.95 (m, 3H),0.69-0.58 (m, 1H). 15 517.0. (400 MHz, CD₃CN, ca 1:1 rotamers) δ 7.87(d, J = 0.4 Hz, 1H), 7.81 (d, J = 0.5 Hz, 1H), 7.61-7.50 (m, 8H),7.35-7.31 (m, 2H), 6.99 (br s, 2H), 4.65-4.56 (m, 3H), 4.54-4.47 (m,1H), 4.33 (t, J = 6.2 Hz, 1H), 4.30-4.21 (m, 2H), 4.11 (t, J = 6.3 Hz,1H), 3.69-3.60 (m, 1H), 3.58-3.42 (m, 3H), 3.04 (d, J = 9.4 Hz, 6H),3.02-2.95 (m, 1H), 2.89 (dd, J = 4.8, 1.5 Hz, 6H), 2.87-2.76 (m, 1H),2.54-2.44 (m, 7H), 2.44-2.34 (m, 1H), 1.96-1.90 (m, 2H), 1.14-1.04 (m,6H), 0.69-0.59 (m, 2H) 16 545.0. (400 MHz, CDCl₃) δ 7.79 (s, 1H),7.58-7.48 (m, 4H), 7.40 (s, 1H), 5.79 (br d, J = 4.1 Hz, 1H), 4.43 (t, J= 6.6 Hz, 2H), 4.30 (d, J = 6.2 Hz, 1H), 4.24 (d, J = 6.2 Hz, 1H),4.06-3.86 (m, 2H), 3.08 (s, 3H), 3.01 (d, J = 4.9 Hz, 3H), 2.49-2.41 (m,1H), 2.07-1.82 (m, 3H), 1.15-1.07 (m, 2H), 1.06-1.00 (m, 1H), 0.85 (d, J= 7.1 Hz, 3H), 0.83 (d, J = 7.1 Hz, 3H), 0.61-0.55 (m, 1H). 17 517.0.(400 MHz, CDCl₃) δ 7.76 (s, 0.5H), 7.75 (s, 0.5H), 7.57-7.48 (m, 4H),7.38 (s, 1H), 5.85-5.77 (m, 1H), 4.62-4.51 (m, 1H), 4.48-4.38 (m, 1H),4.27-4.16 (m, 1H), 3.91-3.70 (m, 2H), 3.07 (s, 1.5H), 3.07 (s, 1.5H),3.01 (d, J = 4.9 Hz, 3H), 2.74-2.58 (m, 1H), 2.47-2.33 (m, 1H),2.22-2.11 (m, 0.5H), 2.11-2.01 (m, 0.5H), 2.01-1.87 (m, 1H), 1.19 (d, J= 6.8 Hz, 1.5H), 1.18 (d, J = 6.8 Hz, 1.5H), 1.13-1.05 (m, 2H),1.04-0.94 (m, 1H), 0.66-0.56 (m, 1H). 18 521.2. (400 MHz, CD₃CN; ca 3:2rotamers) δ 7.88-7.82 (m, 2H), 7.61-7.50 (m, 8H), 7.41 (s, 1H), 7.37 (s,1H), 6.98 (br s, 2H), 5.05-4.96 (m, 1H), 4.93-4.83 (m, 1H), 4.71-4.60(m, 5H), 4.58 (t, J = 6.2 Hz, 1H), 4.52 (t, J = 6.1 Hz, 1H), 4.39-4.32(m, 2H), 4.07-3.96 (m, 1H), 3.89-3.78 (m, 1H), 3.72-3.57 (m, 1H),3.38-3.20 (m, 2H), 3.16 (s, 3H), 3.11 (s, 3H), 2.89 (d, J = 4.8 Hz, 6H),2.43-2.34 (m, 1H), 2.34-2.25 (m, 1H), 1.12-0.96 (m, 6H), 0.74-0.66 (m,1H), 0.65-0.55 (m, 1H). 19 624.1 (400 MHz, CD₃CN) δ 7.83 (s, 1H),7.62-7.53 (m, 4H), 7.38 (s, 1H), 7.00 (br s, 1H), 3.92 (d, J = 4.0 Hz,2H), 3.73-3.62 (m, 2H), 3.50-3.40 (m, 2H), 3.09 (s, 3H), 2.91 (d, J =4.8 Hz, 3H), 2.69-2.57 (m, 1H), 2.43-2.34 (m, 1H), 1.93-1.76 (m, 2H),1.38 (s, 9H), 1.11-1.01 (m, 3H), 0.66-0.56 (m, 1H). 20 498.2 (400 MHz,CDCl₃) δ 8.52 (s, 1H), 8.36 (s, 1H), 7.79 (d, J = 0.9 Hz, 2H), 7.71 (s,1H), 7.55 (s, 0.5H), 7.55 (s, 0.5H), 4.62-4.49 (m, 2H), 4.28-4.17 (m,1H), 3.73-3.53 (m, 2H), 3.06-3.04 (m, 6H), 2.68-2.56 (m, 1H), 2.47 (s,3H), 2.35-2.24 (m, 1H), 2.07-1.86 (m, 2H), 1.39 (d, J = 6.1 Hz, 1.5H),1.36 (d, J = 6.1 Hz, 1.5H), 1.09-0.98 (m, 2H), 0.97-0.87 (m, 1H),0.64-0.53 (m, 1H). 21 498.2 (400 MHz, CDCl₃) δ 8.64-8.52 (m, 1H),8.40-8.34 (m, 1H), 7.84-7.70 (m, 3H), 7.50 (s, 1H), 4.44-4.29 (m, 4H),3.85-3.63 (m, 2H), 3.09 (s, 3H), 3.07 (d, J = 4 Hz, 3H), 2.48 (s, 3H),2.34-2.23 (m, 1H), 2.15-1.94 (m, 2H), 1.28 (s, 3H), 1.07-0.96 (m, 2H),0.92-0.82 (m, 1H), 0.60-0.46 (m, 1H). 23 420.0 (400 MHz, DMSO) δ 9.19(s, 1H), 8.64-8.56 (m, 2H), 8.21 (dd, J = 8.7, 2.6 Hz, 1H), 7.95 (d, J =8.7, 0.6 Hz, 1H), 7.66 (d, 1H), 7.34 (s, 1H), 3.11 (s, 3H), 2.82 (d, J =4.7 Hz, 3H), 2.32-2.20 (m, 1H), 1.04-0.93 (m, 2H), 0.75-0.66 (m, 2H). 24583.1 (400 MHz, CD₃CN) δ 8.39-8.33 (m, 1H), 7.89-7.82 (m, 1H), 7.80 (s,1H), 7.75 (d, J = 8.2 Hz, 1H), 7.37 (br s, 1H), 7.34 (s, 1H), 3.96-3.87(m, 2H), 3.70-3.64 (m, 2H), 3.53-3.40 (m, 2H), 3.09 (s, 3H), 2.93 (d, J= 4.8 Hz, 3H), 2.68-2.58 (m, 1H), 2.44 (s, 3H), 2.41-2.29 (m, 1H),1.92-1.77 (m, 2H), 1.37 (s, 9H), 1.11-0.94 (m, 3H), 0.61-0.49 (m, 1H).25 525.2 (400 MHz, CD₃CN) δ 8.39-8.33 (m, 1H), 7.89-7.83 (m, 1H), 7.81(s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.41-7.32 (m, 2H), 4.20-4.12 (m, 1H),3.95-3.87 (m, 1H), 3.73-3.66 (m, 3H), 3.49-3.41 (m, 1H), 3.10 (s, 3H),2.93 (d, J = 4.8 Hz, 3H), 2.74-2.62 (m, 1H), 2.44 (s, 3H), 2.42-2.32 (m,1H), 1.86 (ddd, J = 14.4, 13.5, 7.1 Hz, 2H), 1.71 (d, J = 1.8 Hz, 3H),1.11-0.96 (m, 3H), 0.60-0.52 (m, 1H). 26 521.2 (400 MHz, CD₃CN) δ 7.83(s, 1H), 7.61-7.50 (m, 4H), 7.39 (s, 1H), 7.00 (br s, 1H), 4.70-4.43 (m,4H), 3.88-3.74 (m, 2H), 3.10 (s, 3H), 2.89 (d, J = 4.8 Hz, 3H),2.41-2.26 (m, 3H), 1.11-1.00 (m, 3H), 0.66-0.57 (m, 1H). 27 631.7 (400MHz, CD₃CN) δ 7.84 (d, J = 0.5 Hz, 1H), 7.63-7.47 (m, 4H), 7.38 (s, 1H),7.01 (s, 1H), 3.81-3.63 (m, 4H), 3.57 (d, J = 9.1 Hz, 2H), 3.13 (s, 3H),3.09 (s, 3H), 2.93-2.86 (m, 3H), 2.41-2.29 (m, 1H), 2.27-2.19 (m, 2H),1.34 (s, 9H), 1.13-0.98 (m, 3H), 0.65-0.54 (m, 1H). 28 514.2 (400 MHz,CDCl₃) δ 8.56 (d, J = 4.6 Hz, 1H), 8.37 (s, 1H), 7.83-7.77 (m, 2H), 7.76(t, J = 2.3 Hz, 1H), 7.54 (d, J = 9.1 Hz, 1H), 4.65 (d, J = 6.8 Hz, 2H),4.33 (t, J = 6.7 Hz, 2H), 3.83-3.64 (m, 2H), 3.21 (s, 3H), 3.11-3.02 (m,6H), 2.48 (s, 3H), 2.42-2.23 (m, 3H), 1.09-0.99 (m, 2H), 0.97-0.85 (m,1H), 0.63-0.51 (m, 1H). 29 532.0 (400 MHz, DMSO) δ 8.76-8.66 (m, 1H),8.27 (s, 1H), 8.01 (s, 1H), 7.70-7.55 (m, 4H), 7.31 (s, 1H), 3.72-3.54(m, 4H), 3.29-3.22 (m, 2H), 3.17 (s, 3H), 3.07 (s, 3H), 2.83 (d, J = 4.6Hz, 3H), 2.39-2.27 (m, 1H), 2.21-2.07 (m, 1H), 2.00 (dt, J = 13.8, 7.4Hz, 1H), 1.08-0.93 (m, 3H), 0.56 (dd, J = 11.0, 5.5 Hz, 1H). 30 574.1(400 MHz, CD₃CN) δ 7.87 (d, J = 3.6 Hz, 1H), 7.65-7.54 (m, 4H), 7.42 (s,1H), 7.05 (s, 1H), 4.07-3.98 (m, 1H), 3.90-3.82 (m, 1H), 3.81-3.71 (m,3H), 3.62 (d, J = 10.2 Hz, 1H), 3.17 (s, 3H), 3.14 (d, J = 2.3 Hz, 3H),2.92 (t, J = 5.4 Hz, 3H), 2.45-2.35 (m, 1H), 2.28-2.12 (m, 2H), 1.76 (s,3H), 1.17-1.00 (m, 3H), 0.71-0.59 (m, 1H). 31 516.94 (400 MHz, CDCl₃) δ7.72 (s, 1H), 7.56-7.48 (m, 4H), 7.37 (s, 1H), 5.92-5.83 (m, 1H),5.07-4.97 (m, 1H), 4.75-4.66 (m, 1H), 4.15-4.06 (m, 1H), 3.70-3.52 (m,2H), 3.04 (s, 3H), 2.99 (d, J = 4.9 Hz, 3H), 2.97-2.88 (m, 1H),2.49-2.34 (m, 1H), 2.05-1.85 (m, 2H), 1.24 (d, J = 6.5 Hz, 1.5H), 1.23(d, J = 6.5 Hz, 1.5H), 1.15-0.98 (m, 3H), 0.63-0.48 (m, 1H). 32^((a))516.9 (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.62-7.53 (m, 4H), 7.44 (s, 1H),5.81 (s, 1H), 4.66-4.53 (m, 2H), 4.30-4.21 (m, 1H), 3.74-3.62 (m, 2H),3.09 (s, 3H), 3.05 (d, J = 5.7 Hz, 3H), 2.72-2.59 (m, 1H), 2.51-2.38 (m,1H), 2.13-1.89 (m, 2H), 1.43 (dd, J = 9.9, 6.1 Hz, 3H), 1.21-1.10 (m,2H), 1.09-1.00 (m, 1H), 0.65 (dt, J = 9.0, 5.5 Hz, 1H). 33^((b)) 516.9(400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.62-7.53 (m, 4H), 7.44 (s, 1H), 5.81(s, 1H), 4.66-4.53 (m, 2H), 4.30-4.21 (m, 1H), 3.74-3.62 (m, 2H), 3.09(s, 3H), 3.05 (d, J = 5.7 Hz, 3H), 2.72-2.59 (m, 1H), 2.51-2.38 (m, 1H),2.13-1.89 (m, 2H), 1.43 (dd, J = 9.9, 6.1 Hz, 3H), 1.21-1.10 (m, 2H),1.09-1.00 (m, 1H), 0.65 (dt, J = 9.0, 5.5 Hz, 1H). 34 504.0 (400 MHz,CDCl₃) δ 8.53 (s, 1H), 7.98 (s, 2H), 7.77 (s, 1H), 7.52 (s, 1H), 7.38(s, 1H), 4.89-4.76 (m, 2H), 4.43-4.32 (m, 2H), 3.81-3.61 (m, 2H), 3.12(d, J = 6.9 Hz, 3H), 3.09 (s, 3H), 2.45-2.31 (m, 1H), 2.17-1.96 (m, 3H),1.19-1.00 (m, 3H), 0.73-0.61 (m, 1H). 35 613.0 (400 MHz, CD₃CN) δ 8.34(dd, J = 1.5, 0.7 Hz, 1H), 7.86-7.72 (m, 3H), 7.37 (s, 1H), 7.28 (br s,1H), 5.46 (br m, 1H), 4.35-4.28 (m, 2H), 4.28-4.22 (m, 2H), 3.85-3.72(m, 2H), 3.27 (d, J = 6.4 Hz, 2H), 3.11 (s, 3H), 2.91 (d, J = 4.8 Hz,3H), 2.42 (s, 3H), 2.39-2.30 (m, 1H), 2.06-1.87 (m, 2H), 1.26 (s, 9H),1.09-0.95 (m, 3H), 0.65-0.56 (m, 1H). 36 533.0 (400 MHz, CDCl₃) δ 7.77(s, 1H), 7.60-7.47 (m, 4H), 7.41 (s, 1H), 5.81 (d, J = 4.4 Hz, 1H), 4.66(t, J = 6.1 Hz, 2H), 4.30 (t, J = 6.1 Hz, 2H), 3.84-3.64 (m, 2H), 3.23(s, 3H), 3.07 (s, 3H), 3.02 (t, J = 6.1 Hz, 3H), 2.48-2.31 (m, 2H),2.30-2.15 (m, 1H), 1.18-1.06 (m, 2H), 1.06-0.96 (m, 1H), 0.68-0.57 (m,1H). ^((a))Unknown absolute stereochemistry, nominally assigned as(2S,3R) enantiomer. ^((b))Unknown absolute stereochemistry, nominallyassigned as (2R,3S) enantiomer.

Biological Data

The in vitro antiviral activity of the compounds of the invention may bedetermined using the following protocols.

HCV Polymerase Inhibition Assay

HCV polymerase reactions were carried out using a modified method ofHowe et al., Antimicrobial Agents and Chemotherapy 2004 48(12):4813-4821. Reactions contained a final concentration of, 0.5% DMSO, 100nM 1b (BK) NS5BΔ21, 20 mM Tris-HCl pH 7.5, 5 mM MgCl₂, 5 mM MnCl₂, 3 mMDTT, 0.05% BSA, 0.2 U/μL RNasin, 10 μg/mL Poly(rC) template, GTP (at Km)and 0.05 μCi/μL ³³P-GTP in a total reaction volume of 50 μL. Compoundswere tested in a three fold dilution series, for example starting from50 μM. Reactions were initiated with the addition of GTP and terminatedafter 90 mM with 50 μL ice cold 0.2 M EDTA. Terminated reactions weretransferred to DEAE 96-well filter plates, unincorporated nucleotideswashed from the filters and 50 μL scintillation fluid added prior toreading on a scintillation counter. The compound concentration thatreduced ³³P-GTP incorporation by 50% (IC₅₀) was calculated usingnon-linear regression.

Representative 1b polymerase IC₅₀ (μM) values for selected compounds ofthe invention in the HCV polymerase inhibition assay are listed asfollows where IC₅₀ (μM) values lie in the ranges:

A (<0.10 μM): 3, 4, 10, 11, 16, 18, 26

B (0.1-0.49 μM): 6, 7, 8, 9, 13, 14, 15, 17, 19, 21, 28, 31, 32, 33, 34

C (0.5-0.99 μM): 5, 20, 22, 25, 27, 30

D (1.0-10.0 μM): 12, 24, 29

HCV Replicon Assays

A genotype 1b (Con 1) subgenomic replicon cell line based on Blight etal., Science 2000 290: 1972-1974, modified to express a Renillaluciferase reporter gene was used to assess antiviral activity of testcompounds. Cell cultures were maintained in a sub-confluent state inDMEM with glutamine, 10% heat-inactivated foetal bovine serum (FBS) andG418 (Geneticin®).

For assay, cells were seeded at a density of 7000 cells/well into 96well tissue culture trays in culture media lacking G418. Compounds weretested in a three fold dilution series, for example starting from 50 uM.After 72 hours incubation at 37° C. and 5% CO₂, Renilla luciferaseactivity was quantified via the Promega Renilla Luciferase orRenilla-Glo™ Luciferase Assay Systems (Promega corporation. The samemethod was employed for replicon assays using subgenomic genotype 1a(H77) and 2a (JFH-1) replicon cell lines with a seeding cell density of5000 cells/well for the 2a cell lines.

The compound concentration that reduced luciferase activity by 50%(EC₅₀) was calculated using non-linear regression. Representativegenotype 1b EC₅₀ values for selected compounds of the invention arelisted as follows where EC₅₀ (μM) values lie in the ranges:

A (<0.10 μM): 3, 4, 5, 8, 9, 10, 11, 13, 14, 16, 19, 20, 21, 24, 26, 27,28, 31, 32, 33, 34

B (0.1-0.49 μM): 7, 17, 18, 22, 25, 36

C (0.5-0.99 μM): 15, 30

D (1.0-10.0 μM): 6, 12, 29, 35

Cytotoxicity Analysis

Cytotoxicity of compounds against genotype 1b replicon cells wasdetermined via metabolism of the vital dye3-(4,5-dimethylthiaxol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, forexample see Watanabe et al., Journal of Virological Methods 199448:257-265). Plates were prepared as described for the HCV Repliconassay and cytotoxicity of the test article was evaluated after threedays. MTT was added to assay plates followed by three hour incubation at37° C. Wells were aspirated to dryness and the formazan dye dissolved bythe addition of isopropanol. Absorbance values were read at 540/690 nm).The compound concentration that reduced cell viability by 50% (CC₅₀) wascalculated using non-linear regression. In general, compounds of theinvention displayed low cytotoxicity with CC₅₀ values of >50 μM.

Cross-Genotype HCV Activity

Cross-genotypic activity of the compounds may be determined in HCVreplicon assays for genotypes such as 1b, 1a and 2a as previouslydescribed and similarly for genotypes 3a, 4a, 5a, 6a and 7a.Multi-genotype HCV polymerase assays include genotypes such as 1b aspreviously described and similarly for genotypes 1a, 2a, 3a, 4a, 5a, 6aand 7a.

Combination Studies in Replicon Cells

A genotype 1b (Con 1) subgenomic replicon cell line based on Blight etal., Science 2000 290: 1972-1974, modified to express a Renillaluciferase reporter gene may be used to assess synergy of testcompounds. Cell cultures were maintained in a sub-confluent state inDMEM with glutamine, 10% heat-inactivated foetal bovine serum (FBS) andG418 (Geneticin®).

For assay, cells are seeded at a density of 7000 cells/well into 96 welltissue culture trays in culture media lacking G418. The compoundconcentration that reduced luciferase activity by 50% (EC₅₀) isdetermined independently for each compound and used to set the range ofconcentrations for the combination experiments. Each compound is testedsingly and in combination using either 3-fold or 5-fold serial dilutionsabove and below the EC₅₀. The ratio of the 2 compounds tested remainedfixed across the titration range. Cytotoxicity of individual compoundsis assessed independently and the titration range below the compoundconcentration that reduced cell viability by 50% (CC₅₀). After 72 hoursincubation at 37° C. and 5% CO₂, Renilla luciferase activity isquantified via the Promega Renilla Luciferase Assay System.

Results are analysed and levels of synergy assessed via generation of 3Dsynergy plots using either MacSynergy™ II (Prichard, M. N., K. R.Aseltine, and C. Shipman, Jr. 1993. MacSynergy II. Version 1.0. User'smanual. University of Michigan, Ann Arbor.) or by calculation of acombination index (CI) using the CalcuSyn software package (version 2.1)which performs multiple drug dose-effect calculations using the MedianEffect methods (Chou T-C. Drug Combinations Studies and Their SynergyQuantification Using the Chou-Talalay Method. Cancer Research 2010; 70440-446.). This model allows the calculation of a combination index (CI)which is a quantitative definition of an additive effect (CI=1),synergism (CI<1) or antagonism (CI>1) for different drug combinations.Theoretical additive interactions are individually calculated from thedose-response curves for each compound used. This surface is subtractedfrom the actual dose-response curve to give regions of non-additiveinteractions. Combination indices can be expressed for different binarycombinations of compounds at specific concentrations.

Aqueous Solubility

Test compounds prepared in DMSO were screened in duplicate over a rangeof concentrations (1.6-100 ug/mL) in different aqueous media (forexample a pH6.5 buffers which are relevant to the stomach and upperregions of the small intestine and therefore important when predictingthe amount of drug likely to be in solution following oraladministration). Test compounds were serially diluted in 100% DMSOranging from 10-0.16 mg/mL. These titrated DMSO stocks were then furtherdiluted 1:100 with assay buffer and added to test plates (UV StarGriener 384 well plates), maintaining the DMSO concentration at 1%. Thesolubility concentration range was determined by interpretingNEPHELOstar laser nephelometery readings taken after a 30 minuteincubation at 25° C. A compound is considered to have good solubilitywhen the value is >25 ug/mL.

A representative example of the invention having an optionallysubstituted 4-membered heterocyclic moiety i.e. Compound (14) wasselected for comparative solubility studies as against Compounds A-Dbelow. Surprisingly, only Compound 14 was found to have good solubilityat pH 6.5 as demonstrated by the results obtained and provided in Table2 below. In comparison Compounds A-D were considered to be poorlysoluble.

TABLE 2 Compounds and solubility at pH 6.5 Solubility at pH 6.5 ObservedLCMS m/z [M + H]⁺ No. Structure (μg/mL) and ¹H NMR data 14

 25-50  Refer to Table 1. A

1.6-3.1 ESI-MS m/z calculated for [M + H]⁺: 487.2 found: 487.1. (400MHz, CDCl₃): δ 7.70 (s, 1H), 7.55-7.49 (m, 4H), 7.32 (s, 1H), 5.77 (s,1H), 3.78 (d, J = 7.5 Hz, 2H), 3.05 (s, 3H), 3.01 (d, J = 4.9 Hz, 3H),2.53 (dt, J = 15.3, 7.7 Hz, 1H), 2.46-2.35 (m, 1H), 2.07-1.93 (m, 2H),1.93-1.71 (m, 3H), 1.71-1.61 (m, 1H), 1.22-1.05 (m, 2H), 0.99-0.85 (m,1H), 0.71-0.62 (m, 1H) B

3.1-6.3 ESI-MS m/z calculated for [M + H]⁺: 473.1; found: 473.1. ¹H NMR(400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.64-7.51 (m, 4H), 7.42 (s, 1H), 5.86(brs, 1H), 3.66 (ddd, J = 20.9, 14.2, 7.2 Hz, 2H), 3.16 (s, 3H), 3.06(d, J = 4.9 Hz, 3H), 2.56-2.44 (m, 1H), 1.20-1.06 (m, 3H), 1.04-0.96 (m,1H), 0.72-0.61 (m, 1H), 0.57 (d, J = 7.9 Hz, 2H), 0.30-0.21 (m, 2H). C

<1.6 ESI-MS m/z calculated for [M + H]⁺: 503.2; found: 503.0. ¹H NMR(400 MHz, CDCl₃) δ 7.79 (d, J = 14.6 Hz, 1H), 7.64-7.50 (m, 4H), 7.39(s, 1H), 5.82 (brs, 1H), 3.98-3.68 (m, 5H), 3.47 (dd, J = 8.9, 5.3 Hz,1H), 3.09 (s, 3H), 3.05 (d, J = 4.9 Hz, 3H), 2.56-2.39 (m, 2H),2.14-1.98 (m, 1H), 1.89 (dt, J = 20.1, 6.4 Hz, 1H), 1.24-1.09 (m, 2H),1.09- 1.00 (m, 1H), 0.74-0.67 (m, 1H). D

<1.6 ESI-MS m/z calculated for [M + H]⁺: 531.2; found: 531.1. ¹H NMR(400 MHz, CDCl₃) δ 7.75 (s, 1H), 7.63-7.51 (m, 4H), 7.40 (s, 1H), 5.88(brd, J = 4.5 Hz, 1H), 4.00-3.89 (m, 2H), 3.87-3.76 (m, 2H), 3.46-3.30(m, 2H), 3.09 (s, 3H), 3.04 (d, J = 4.9 Hz, 3H), 2.52-2.39 (m, 1H),1.71-1.49 (m, 5H), 1.39-1.20 (m, 2H), 1.20-0.99 (m, 3H), 0.70-0.58 (m,1H).

Representative solubility ranges at pH 6.5 for selected compounds of theinvention are as follows:

A (12.5-25 μg/mL): 3, 20, 24, 29, 35

B (25-50 μg/mL): 8, 9, 26, 32

C (50-100 μg/mL): 17, 18, 28, 30, 33, 36

D (>100 μg/mL): 21, 25

Metabolic Stability Assay

The in vitro metabolic stability of compounds of the invention wastested using human liver microsomes as a preliminary indication of thelikely in vivo metabolic clearance. The metabolic stability assay wasperformed by incubating test compounds individually (1 μM) with humanliver microsomes at 37° C. and 0.4 mg/mL protein concentration. Themetabolic reaction was initiated by the addition of anNADPH-regenerating system (i.e. NADPH is the cofactor required forCYP450-mediated metabolism) and quenched at various time points over the60 min incubation period by the addition of acetonitrile. Additionalsamples with the dual co-factors, NADPH and UDPGA (the latter being theco-factor for glucuronidation), can be included in the incubation forqualitative assessment of the potential for glucuronide formation.Control samples (containing neither NADPH nor UDPGA) were included tomonitor for potential degradation in the absence of cofactors.Concentrations of each test compound were determined by LC-MS or UPLC-MSrelative to calibration standards. Test compound concentration versustime data were fitted to an exponential decay function to determine thefirst-order rate constant for substrate depletion. In cases where cleardeviation from first-order kinetics was evident, only the initial linearportion of the profile was utilised to determine the degradation rateconstant (k). Each substrate depletion rate constant can then be used tocalculate: a degradation half-life, an in vitro intrinsic clearancevalue (CL_(int), in vitro); a predicted in vivo hepatic intrinsicclearance value (CL_(int)) and a predicted in vivo hepatic extractionratio (E_(H)). The predicted hepatic extraction ratios (E_(H)) obtainedwere used to classify compounds as low (<0.3), intermediate (0.3-0.7),high (0.7-0.95) or very high (>0.95) extraction compounds. A compound isconsidered to have good metabolic stability when the E_(H) value is lowor intermediate (i.e. E_(H)<0.7). Calculations, scaling parameters andclassifications are essentially as described in the literature (forexample see (1993) Physiological parameters in laboratory animal andhumans. Pharmaceutical Research, 10:1093-1095; (Obach, 1999, Drug Metab.Dispos. 27: 1350-1359).

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication, orinformation derived from it, or to any matter which is known, is not,and should not be taken as an acknowledgement or admission or any foul;of suggestion that prior publication, or information derived from it, orknown matter forms part of the common general knowledge in the field ofendeavour to which this specification relates.

The invention claimed is:
 1. A compound of formula (I), salts, N-oxides,solvates, hydrates, racemates, enantiomers or diastereomers thereof:

wherein Z₁ and Z₂ are each independently selected from the groupconsisting of C—H, C-halo, C—C₁₋₄alkyl, C—C₁₋₄alkylhalo, C—C₁₋₄alkoxy,C—C₁₋₄alkoxyhalo and N; R₁ is selected from the group consisting of H,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, halo, C₁₋₄alkylhalo,C₁₋₄alkoxyhalo, C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, 5-6-memberedheterocyclyl and 5-6 membered heteroaryl and wherein alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, heterocyclyl and heteroaryl is optionallysubstituted; R₂ is a substituted 4-membered heterocyclic ring; R₃ isselected from the group consisting of aryl, aryl-X-aryl,aryl-X-heteroaryl, heteroaryl, heteroaryl-X-heteroaryl, andheteroaryl-X-aryl wherein X is [C(R₅)₂]_(p), O, S, S(═O), SO₂, NR₅, C═O,CF₂, C(═O)NR₅ or NR₅C(═O) wherein p is 1, 2 or 3 and wherein aryl andheteroaryl is optionally substituted; R₄ is H, C₁₋₄alkyl, C₂alkenyl,C₂alkynyl, or C₃₋₇cycloalkyl; R₅ in each occurrence is independently Hor optionally substituted C₁₋₆alkyl; m represents an integer selectedfrom the group consisting of 0, 1, 2, 3, 4, 5 and 6; and each (CH₂)moiety when present is independently optionally substituted with one ortwo substituents; and further when m is an integer selected from thegroup consisting of 1, 2, 3, 4, 5 and 6 then one or more (CH₂) isoptionally replaced with O, C═O, NH, optionally substituted NC₁₋₆alkyl,S, S═O or SO₂.
 2. The compound according to claim 1 wherein R₂ is anoptionally substituted oxetane or azetidine ring.
 3. The compoundaccording to claim 1 wherein the compound is of formula (Ia), salts,N-oxides, solvates, hydrates, racemates, enantiomers or diastereomersthereof:

wherein Z₁, Z₂, R₁, R₃, R₄, R₅ and m are as previously defined; W₁ isCR^(a) or N; W₂, W₃ and W₄ are each independently O, NR^(b), S, S═O,SO₂, C═O or CR^(c)R^(d); and R^(a), R^(b), R^(c) and R^(d) are eachindependently H or an optional substituent; and with the proviso thatone of W₁, W₂, W₃ and W₄ is a heteroatom selected from the groupconsisting of O, NR^(b) and S and the three remaining are independentlyCR^(a) in the case of W₁ and CR^(c)R^(d) in the case of any one of W₂,W₃ or W₄.
 4. The compound according to claim 1 wherein (CH)_(m) is anoptionally substituted methylenyl, ethylenyl or propylenyl moiety. 5.The compound according to claim 1 selected from the group consisting of:3)5-cyclopropyl-N-methyl-2-(4-methylphenyl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide;4)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)[3-(oxetan-2-yl)propyl]amino}-2H-indazole-3-carboxamide;5)5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide;6)6-{[2-(azetidin-3-yl)ethyl](methylsulfonyl)amino}-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide;7)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{[2-(1-methylazetidin-3-yl)ethyl](methylsulfonyl)amino}-2H-indazole-3-carboxamide;8)6-{[2-(1-acetylazetidin-3-yl)ethyl](methylsulfonyl)amino}-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide;9)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{[2-(2-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2H-indazole-3-carboxamide;10)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide;11)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{[2-(3-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2H-indazole-3-carboxamide;12)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{[(3-methyloxetan-3-yl)methyl](methylsulfonyl)amino}-2H-indazole-3-carboxamide;13)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)[2-(oxetan-2-yl)ethyl]amino}-2H-indazole-3-carboxamide;14)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)(oxetan-3-ylmethyl)amino]-2H-indazole-3-carboxamide;15)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)[2-(oxetan-3-yl)propyl]amino}-2H-indazole-3-carboxamide;16)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl){2-[3-(propan-2-yl)oxetan-3-yl]ethyl}amino]-2H-indazole-3-carboxamide;17)3,5-anhydro-1-{[2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)-2H-indazol-6-yl](methylsulfonyl)amino}-1,2,4-trideoxy-4-methylpentitol;18)2-(4-chlorophenyl)-5-cyclopropyl-6-{[2-fluoro-2-(oxetan-3-yl)ethyl](methylsulfonyl)amino}-N-methyl-2H-indazole-3-carboxamide;19) tert-butyl3-(2-{[2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)-2H-indazol-6-yl](methylsulfonyl)amino}ethyl)azetidine-1-carboxylate;20)5-cyclopropyl-N-methyl-6-{[2-(2-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide;21)5-cyclopropyl-N-methyl-6-{[2-(3-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide;22)2-(4-chlorophenyl)-5-cyclopropyl-6-[2-(3-hydroxyazetidin-1-yl)ethyl-methylsulfonyl-amino]-N-methyl-indazole-3-carboxamide;24) tert-butyl3-[2-[[5-cyclopropyl-3-(methylcarbamoyl)-2-(5-methyl-2-pyridyl)indazol-6-yl]-methylsulfonyl-amino]ethyl]azetidine-1-carboxylate;25)6-[2-(1-acetylazetidin-3-yl)ethyl-methylsulfonyl-amino]-5-cyclopropyl-N-methyl-2-(5-methyl-2-pyridyl)indazole-3-carboxamide;26)2-(4-chlorophenyl)-5-cyclopropyl-6-[2-(3-fluorooxetan-3-yl)ethyl-methylsulfonyl-amino]-N-methyl-indazole-3-carboxamide;27) tert-butyl3-[2-[[2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)indazol-6-yl]-methylsulfonyl-amino]ethyl]-3-methoxy-azetidine-1-carboxylate;28)5-cyclopropyl-6-[2-(3-methoxyoxetan-3-yl)ethyl-methylsulfonyl-amino]-N-methyl-2-(5-methyl-2-pyridyl)indazole-3-carboxamide;29)2-(4-chlorophenyl)-5-cyclopropyl-6-[2-(3-methoxyazetidin-3-yl)ethyl-methylsulfonyl-amino]-N-methyl-indazole-3-carboxamide;30)6-[2-(1-acetyl-3-methoxy-azetidin-3-yl)ethyl-methylsulfonyl-amino]-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-indazole-3-carboxamide;31)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[2-[-2-methyloxetan-3-yl]ethyl-methylsulfonyl-amino]indazole-3-carboxamide;32)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[{2-[(2S,3R)-2-methyloxetan-3-yl]ethyl}(methylsulfonyl)amino]-2H-indazole-3-carboxamide;33)2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[{2-[(2R,3S)-2-methyloxetan-3-yl]ethyl}(methylsulfonyl)amino]-2H-indazole-3-carboxamide;34)2-(5-chloro-2-pyridyl)-5-cyclopropyl-N-methyl-6-[methylsulfonyl-[2-(oxetan-3-yl)ethyl]amino]indazole-3-carboxamide;35) tert-butylN-[[3-[2-[[5-cyclopropyl-3-(methylcarbamoyl)-2-(5-methyl-2-pyridyl)indazol-6-yl]-methylsulfonyl-amino]ethyl]oxetan-3-yl]methyl]carbamate;36)2-(4-chlorophenyl)-5-cyclopropyl-6-[2-(3-methoxyoxetan-3-yl)ethyl-methylsulfonyl-amino]-N-methyl-indazole-3-carboxamide;and salts, N-oxides, solvates, hydrates, racemates, enantiomers ordiastereomers thereof.
 6. A pharmaceutical agent comprising the compoundaccording to claim 1 or salts, N oxides, solvates, hydrates, racemates,enantiomers or diastereomers thereof and optionally another compoundwherein the another compound is an HCV antiviral agent.
 7. Thepharmaceutical agent according to claim 6 additionally comprising atleast one immunomodulatory agent.
 8. The pharmaceutical agent accordingto claim 6 wherein the HCV antiviral agent is selected from the groupconsisting of Ribavarin, an NS5B inhibitor, an NS3/4A protease inhibitorand an NS5A inhibitor.
 9. The pharmaceutical agent according to claim 6,adapted for oral administration.
 10. An HCV polymerase inhibitorcomprising the compound according to claim 1 or salts, N-oxides,solvates, hydrates, racemates, enantiomers or diastereomers thereof andoptionally another HCV antiviral agent.
 11. The HCV polymerase inhibitoraccording to claim 10 additionally comprising at least oneimmunomodulatory agent.
 12. The HCV polymerase inhibitor according toclaim 10 wherein the HCV antiviral agent is selected from the groupconsisting of Ribavarin, an NS5B inhibitor, an NS3/4 protease inhibitorand an NS5A inhibitor.
 13. The HCV polymerase inhibitor according toclaim 10 adapted for oral administration.
 14. A pharmaceuticalcomposition comprising the compound according to claim 1 or salts,N-oxides, solvates, hydrates, racemates, enantiomers or diastereomersthereof, a pharmaceutically acceptable carrier and optionally anothercompound wherein the another compound is an HCV antiviral agent.
 15. Thepharmaceutical composition according to claim 14 additionally comprisingat least one immunomodulatory agent.
 16. The pharmaceutical compositionaccording to claim 14 wherein the HCV antiviral agent is selected fromthe group consisting of Ribavarin, an NS5B inhibitor, an NS3/4 proteaseinhibitor and an NS5A inhibitor.
 17. The pharmaceutical compositionaccording to claim 14 adapted for oral administration.
 18. A method fortreating a Flaviviridae viral infection, wherein the method comprisesadministering an effective amount of: the compound according to claim 1or salts, N-oxides, solvates, hydrates, racemates, enantiomers ordiastereomers thereof and optionally another compound wherein theanother compound is an HCV antiviral agent; a pharmaceutical agentcomprising the compound according to claim 1 or salts, N oxides,solvates, hydrates, racemates, enantiomers or diastereomers thereof andoptionally another compound wherein the another compound is an HCVantiviral agent; a HCV polymerase inhibitor comprising the compoundaccording to claim 1 or salts, N-oxides, solvates, hydrates, racemates,enantiomers or diastereomers thereof and optionally another compoundwherein the another compound is an HCV antiviral agent; or apharmaceutical composition comprising the compound according to claim 1or salts, N-oxides, solvates, hydrates, racemates, enantiomers ordiastereomers thereof, a pharmaceutically acceptable carrier andoptionally another compound wherein the another compound is an HCVantiviral agent.
 19. The method according to claim 18 wherein theadministration is oral administration.
 20. The method according to claim18 wherein the Flaviviridae viral infection is a HCV infection.
 21. Amethod of inhibiting an RNA-dependent RNA polymerase activity of anenzyme NS5B, encoded by HCV, comprising exposing the enzyme NS5B to aneffective amount of the compound according to claim 1 or salts,N-oxides, solvates, hydrates, racemates, enantiomers or diastereomersthereof and optionally another compound wherein the another compound isan HCV antiviral agent.
 22. A method of inhibiting HCV replicationcomprising exposing a cell infected with HCV to an effective amount ofthe compound according to claim 1 and optionally another compoundwherein the another compound is an HCV antiviral agent.
 23. Apharmaceutical composition comprising the compound according to claim 1or salts, N-oxides, solvates, hydrates, racemates, enantiomers ordiastereomers thereof, a pharmaceutically acceptable carrier andoptionally another compound wherein the another compound is an HCVantiviral agent selected from the group consisting of Ribavarin, an NS5Binhibitor, an NS3/4A protease inhibitor and an NS5A inhibitor.
 24. Thepharmaceutical composition according to claim 23 additionally comprisingat least one immunomodulatory agent.
 25. A method for treating a HCVinfection, wherein the method comprises administering an effectiveamount of the pharmaceutical composition according to claim 23 to asubject in need thereof.
 26. A process for producing the compoundaccording to claim 1 comprising the step of coupling a compound offormula (II):

with a compound of general formula (III) under coupling conditions;wherein W is hydroxyl, mesylate, tosylate, triflate or halo; and Z₁, Z₂,R₁, R₂, R₃, R₄, R₅ and (CH)_(m) are as defined in claim
 1. 27. Acompound of formula (II) as defined in claim 26 wherein R₃ is anoptionally substituted 2-pyridyl.